Search

To examine the possible causative association between Crohn disease (CD) and the T-cell surface glycoprotein CD5 and to ascertain whether sphingomyelin (SM) functions as a mediator. We conducted a two-step Mendelian randomization (MR) study to further explore the pathogenesis of Crohn and its related targets. MR study was performed on CD5 and CD using summary-level data from a genome-wide association study. Additionally, by employing a two-step MR study method, we determined that SM might mediate the causal effect of CD5 on CD. There was a favorable correlation between the surface glycoprotein CD5 on T cells and vulnerability to CD, and SM mediated the causal effect of CD5 on CD (the mediating effect accounts for 9.2%). Our study revealed that CD5 and CD are causally related, with SM mediating a small fraction of the impact (approximately 9.2%). The mediating function of SM in the link between CD5 and CD is anticipated to be realized through the regulation of immune cell transportation, apoptosis of intestinal barrier cells, and maintenance of the intestinal microenvironment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin's lymphoma (NHL), is substantially heterogeneous. Approximately 5-10% of DLBCLs express CD5, which makes CD5 + DLBCL a rare subgroup. Different studies have shown that CD5 + DLBCL patients are often older and female and have higher lactate dehydrogenase levels, an Eastern Cooperative Oncology Group (ECOG) performance status > 1, and higher International Prognostic Index (IPI) scores. Moreover, patients often have advanced stage disease with a high incidence of central nervous system (CNS) relapse and bone marrow involvement. CD5 + DLBCL cells are more likely to express MYC, BCL-2, and MUM-1, less likely to express CD10, and most belong to the activated B-cell-like (ABC) subtype. The potential mechanisms underlying the poor prognosis of CD5 + DLBCL patients may be related to CD5-mediated B-cell receptor (BCR)-dependent and -independent pathways. The efficacy of the traditional rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen is unsatisfactory in CD5 + DLBCL patients. Despite supporting evidence from retrospective studies, it is currently unclear whether dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) can improve outcomes in this population. Several new drugs, such as Bruton tyrosine kinase inhibitors (BTKi), BCL-2 inhibitors, and CXCR4 antagonists, as well as immunotherapy, may help to improve the prognosis of CD5 + DLBCL patients, but additional clinical explorations are needed to determine the optimal therapeutic strategy for this disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunologic self-tolerance involves signals from co-inhibitory receptors. Several T cell co-inhibitors, including PD-1, are expressed upon activation, whereas CD5 and BTLA are expressed constitutively. The relationship between constitutively expressed co-inhibitors and when they are needed is unknown. Deletion of Btla demonstrated BTLA regulates CD5 expression. Loss of BTLA signals, but not signalling by its ligand, HVEM, leads to increased CD5 expression. Higher CD5 expression set during thymic selection is associated with increased self-recognition, suggesting that BTLA might be needed early to establish self-tolerance. We found that BTLA and PD-1 were needed post-thymic selection in recent thymic emigrants (RTE). RTE lacking BTLA caused a CD4 T cell and MHC class II dependent multi-organ autoimmune disease. Together, our findings identify a negative regulatory pathway between two constitutively expressed co-inhibitors, calibrating their expression. Expression of constitutive and induced co-inhibitory receptors is needed early to establish tolerance in the periphery for RTE.

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare condition characterized by benign localized lymphadenopathy and clinical symptoms such as fever, sore throat, odynophagia, and leukopenia. Though the etiology of KFD is unknown, this condition is similar to viral infection, including increased infiltration of activated plasmacytoid dendritic cells. KFD exhibits three histological phases that reflect its progression status: proliferative, necrotic, and xanthomatous lesions. The expression loss of pan T-cell markers, such as CD2, CD5, and CD7, of infiltrating T-cells is observed in KFD cases, complicating the distinction from T-cell lymphoma. However, reports on the loss of their expression in KFD have been limited. Furthermore, the precise population of the T-cell subset in KFD is still unclear. Here, we focused on surface markers and transcription factors for T-cell differentiation and analyzed them immunohistochemically in 46 KFD cases. We observed diminished CD5 expression of CD8-positive (CD5 dim CD8+) T-cells in the proliferative lesion of KFD cases. Furthermore, these CD5 dim CD8+ T-cells expressed T-BET, a master regulator of type 1 helper T-cells. The upregulation of T-BET and downregulation of CD5 in CD8+ T-cells causes dysregulated activation and proliferation of CD8+ T-cells, potentially contributing to the unique histopathological features of KFD. Recognizing the frequent infiltration of T-BET-positive CD5 dim CD8+ T-cells in KFD is important for distinguishing it from mature T-cell lymphoma. Our findings suggest that the immune response in KFD shares similarities with viral infections and highlight the importance of characterizing T-BET-positive CD5 dim CD8+ T-cell populations for understanding KFD pathogenesis.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4 dim /CD5 bright proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin. Somatic mutations of BTK/PLCG2, detected in 57% of progressing cases, were significantly enriched in PF with a 3-fold greater allele frequency than the non-PF fraction, suggesting a BTK/PLCG2-mutated reservoir resident within the proliferative compartments. PF increase was also present in BTK/PLCG2-unmutated cases at progression, indicating that PF evaluation could represent a marker of CLL progression under ibrutinib. Furthermore, we evidence different transcriptomic profiles of PF at progression in cases with or without BTK/PLCG2 mutations, suggestive of a reactivation of B-cell receptor signaling or the emergence of bypass signaling through MYC and/or Toll-Like-Receptor-9. Clinically, longitudinal monitoring of the CXCR4 dim /CD5 bright PF by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy., (© 2024. The Author(s).)

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(-) cyclin D1(+) SOX11(-), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce T cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a chimeric antigen receptor (CAR) targeting CD5, a prominent pan-T cell antigen, induces rapid internalization and complete loss of the CD5 protein on T cells, protecting them from self-targeting. Notably, exposure of healthy and malignant T cells to CD5.CART cells induces similar internalization of CD5 on target cells, transiently shielding them from cytotoxicity. However, this protection is short-lived, as sustained activity of CD5.CART cells in patients with T cell malignancies results in full ablation of CD5 + T cells while sparing healthy T cells naturally lacking CD5. These results indicate that continuous downmodulation of the target antigen in CD5.CART cells produces effective fratricide resistance without undermining their on-target cytotoxicity., Competing Interests: Declaration of interests M.M. and M.K.B. are co-founders of March Biosciences, have equity, and serve on the advisory board for March Biosciences. M.K.B. is a cofounder and equity holder in AlloVir, Inc. and Marker Therapeutics. M.K.B. has equity in Tessa Therapeutics Ltd. and March Biosciences and serves on advisory boards for Marker Therapeutics, Allogene, Walking Fish, Abintus, Tessa Therapeutics, Athenex, ONK Therapeutics, Coya Therapeutics, Triumvira, Adaptimmune, Vor Therapeutics, and TScan. M.M. serves on the scientific advisory board of NKILT and receives research support from Fate Therapeutics and honoraria from Amgen and Galapagos NV. L.C.H. provides consulting services to March Biosciences. M.M. and M.K.B. have patent applications and a granted patent related to this work. An up-to-date declaration of interests for the listed authors can be found at https://www.bcm.edu/academic-centers/cell-and-gene-therapy/research/disclosure-of-outside-interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, cases of carcinoma showing thymus-like differentiation (CASTLE) occurring in major salivary glands have been identified. To assess the diagnostic value of CD5 immunohistochemistry in distinguishing salivary CASTLE from other types of salivary gland tumors, we evaluated CD5 expression in 109 salivary gland tumors, encompassing 23 different histological types, including salivary CASTLE. In addition, we reviewed 10 previously reported cases of salivary CASTLE. Most salivary CASTLE cases (10/11, 91%) showed strong CD5 expression. In contrast, 104 of 108 (96%) non-salivary CASTLE tumors were negative for CD5, while the remaining four tumors (3.7%), all of which were histologically Warthin tumors, showed focal positivity for CD5 with weak to moderate intensity. In conclusion, the findings in this study support the potential use of CD5 immunohistochemistry for distinguishing salivary CASTLE from other histological types of salivary gland tumors. Aberrant CD5 expression in this tumor may be linked to the tumor microenvironment., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The function of CD5 protein in T cells is well documented, but regulation of its surface-level expression has yet to be fully understood. However, variation in its surface expression is associated with various immunopathological conditions and haematological malignancies. Briefly, expression of an alternate exon E1B of a human endogenous retroviruses (HERV) origin directly downregulates the conventional transcript variant (E1A), as its expression leads to the retention of the resultant protein at the intracellular level (cCD5). A separate promoter governs the expression of E1B and may be influenced by different transcription factors. Hence, we performed in silico transcription factor binding site (TFBS) analysis of the 3 kb upstream region from TSS of exon E1B and found five putative DREs (Dioxin Response elements) with good similarity scores. Further, we observed the upregulation in E1B expression after the exposure of BaP (a dioxin) and the reduction of E1A expression and their respective protein, i.e. sCD5 and cCD5. The binding of AHR at the predicted DRE sites was confirmed by ChIP qPCR and AHR specific inhibitor and gene silencing studies suggested the involvement of AHR in exonal switch. This study indicates that the polycyclic aromatic hydrocarbon decreases the sCD5 expression by upregulating alternative exon expression, which may adversely affect the overall T cell functions., Competing Interests: Declaration of competing interest No conflicts of interest declared., (Copyright © 2024 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze the clinical characteristics and prognosis of patients with CD5 + diffuse large B-cell lymphoma (DLBCL)., Methods: The clinical data of 161 newly treated DLBCL patients in Gansu Provincial Hospital from January 2013 to January 2020 were retrospectively analyzed. According to CD5 expression, the patients were divided into CD5 + group and CD5 - group. The clinical characteristics and prognosis of the two groups were statistically analyzed., Results: The median age of patients in CD5 + group was 62 years, which was higher than 56 years in CD5 - group ( P =0.048). The proportion of women in CD5 + group was 62.96%, which was significantly higher than 41.79% in CD5 - group ( P =0.043). The proportion of patients with IPI score > 2 in CD5 + group was 62.96%, which was higher than 40.30% in CD5 - group ( P =0.031). Survival analysis showed that the median overall survival and progression-free survival time of patients in CD5 + group were 27(3-77) and 31(3-76) months, respectively, which were both shorter than 30(5-84) and 32.5(4-83) months in CD5 - group ( P =0.047, P =0.026). Univariate analysis showed that advanced age, positive CD5 expression, triple or double hit at initial diagnosis, high IPI score and no use of rituximab during chemotherapy were risk factors for the prognosis of DLBCL patients. Further Cox multivariate regression analysis showed that these factors were also independent risk factors except for advanced age., Conclusion: CD5 + DLBCL patients have a worse prognosis than CD5 - DLBCL patients. Such patients are more common in females, with advanced age and high IPI score, which is a special subtype of DLBCL.

Aims: To investigate the clinicopathological features, immunophenotypes and differential diagnosis of CD5-positive splenic marginal zone lymphoma (SMZL)., Methods: We retrospectively analysed 16 CD5-positive cases of SMZL. Assess their clinicopathological features and survival outcomes to evaluate their similarities and differences with a control group of 25 CD5-negative cases of SMZL., Results: Compared with CD5-negative patients, CD5-positive SMZL tends to be more prone to B symptoms, peripheral lymphadenopathy and extranodal infiltration, high Ann Arbor stage, high International Prognostic Index scores, high serum lactic dehydrogenase and high rates of bone marrow involvement. The 5-year survival rate was significantly shorter than that of the CD5-negative group (52.1% and 81.8%, respectively)., Conclusions: There are many similarities between CD5-positive SMZL and classical CD5-negative SMZL in clinical presentations, morphology and immunohistochemistry, but the former may have a more aggressive clinical course with a poorer prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To analyze the clinicopathological features of salivary carcinoma showing thymus-like differentiation(CASTLE). Methods: Cases diagnosed with salivary CASTLE from January 2020 to December 2023 were collected and selected from the Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. A total of 7 cases of salivary CASTLE were identified. All the cases originated from parotid. There were 3 males and 4 females. The patients' age range was 11-70 years.The clinical, microscopic, immunohistochemical and prognostic features of these cases were analyzed. Results: The duration of disease ranged from 1 month to 1 year, and 1 patient had facial numbness and 1 with swelling sensation occasionally. Radiographically, 4 cases showed malignant signs. Microscopically, 4 cases involved in parotid gland, and all the tumors had different degrees of lymphoid tissue background. The tumor cells arranged in nests, 5 cases with lymphoepithelial carcinoma-like and 2 cases with squamous cell carcinoma morphology. The tumor cells expressed CD5 and CD117 proteins diffusely in lymphoepithelial carcinoma-like cases. However, the tumor cells expressed CD5 diffusely and CD117 focally in cases with squamous cell carcinoma morphology. All the cases had no Epstein-Barr virus infection. Among the 6 patients with follow-up information, all of them underwent postoperative radiotherapy, and none of them had local recurrence and lymph node metastasis. Conclusions: Salivary CASTLE is a rare tumor, it should be distinguished from lymphoepithelial carcinoma and squamous cell carcinoma. The patients often have better prognosis and CD5 protein expression has a valuable role in the differential diagnosis.

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c + CD5 + DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5 + DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5 hi T helper and CD8 + T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5 + DCs are an essential component of optimal ICB therapy.

Zonulin is a physiologic epithelial and endothelial permeability modulator. Zonulin increases antigen trafficking from the gut lumen into the bloodstream and in between body compartments, a mechanism linked to many chronic inflammatory diseases. Upon its initial discovery, it was noted that zonulin was not a single protein, but rather a family of structurally and functionally related proteins referred to as the zonulin family proteins (ZFPs). ZFPs are members of the mannose associated serine proteases (MASP) family and are the result of high mutation rates leading to many zonulin polymorphisms. Pre-haptoglobin 2, the precursor of haptoglobin 2, was identified as the first eukaryotic member of the ZFPs, and properdin, a key positive regulator of the alternative pathway, as a second member. In this study, we report two additional proteins that are likely ZFPs. Human coagulation factor X (FX) and CD5 antigen-like (CD5L). Both FX and CD5L recombinant proteins were detected by anti-zonulin antibody in Western immunoblot analysis, and both proteins decreased epithelial barrier competency of Caco-2 cell monolayers as established by the Trans Epithelial Electrical Resistance (TEER) assay. These results indicate that FX and CD5L have structural and functional similarities with previously identified ZFPs and, therefore, can be considered new members of this family of proteins., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. TK was financially supported by The Uehara Memorial Foundation Overseas Postdoctoral Fellowships and The Ito Foundation for the Promotion of Medical Science Travel Grants for Overseas Exchange. Other authors have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Neutrophil extracellular trap (NET) has been demonstrated to play important roles in the pathogenesis and progression of rheumatoid arthritis (RA). Emerging evidence indicates that ligation of signal inhibitory receptor on leukocytes-1 (SIRL-1) can dampen Fc receptor-induced reactive oxygen species (ROS) production in primary human neutrophils by reducing extracellular signal-regulated kinase (ERK) activation. The current study aimed to determine the regulatory effects of SIRL-1 on the NET formation and ROS production by comparing RA patients and healthy controls (HC)., Methods: Multiple assays were employed to detect the expression level of SIRL-1, including immunohistochemical staining, quantitative reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. Peripheral blood neutrophils from both HC and RA patients were freshly isolated. The NET formation was assessed spontaneously before and after exposure to serum samples from HC and RA patients, respectively. The quantification of NET formation was determined by fluorescence microscopy and Spectra Max M5 fluorescent plate reader. The ROS production was examined by flow cytometry., Results: The expression level of SIRL-1 in peripheral blood neutrophils was decreased in RA, comparing to HC. The RA-originated neutrophils showed higher levels of ROS production and NET formation. Ligation of SIRL-1 to neutrophils suppressed ROS production and NET formation. Stimulation of neutrophils with severe anti-cyclic citrullinated peptides (CCP) induced NET formation, which could be inhibited by application of SIRL-1 ligation., Conclusion: The current study identified SIRL-1 differentially expressed in neutrophils between RA and HC. Ligation of SIRL-1 inhibited ROS production and NET formation. Downregulation of SIRL-1 showed correlation with upregulation of NET formation in RA. These findings showed the regulation of SIRL-1 on NET formation and provided a potential therapeutic target for RA., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

IL-15 induces the proliferation of memory CD8 + T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8 + T cells. However, whether CD5 directly regulates IL-15-induced proliferation of human memory CD8 + T cells is unknown. In the current study, we demonstrate that human memory CD8 + T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8 + T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8 + T cells. Importantly, we found that IL-15-induced proliferation of human memory CD8 + T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15-induced proliferation of human memory CD8 + T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15-induced proliferation of human memory CD8 + T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15-induced proliferation of human memory CD8 + T cells by inhibiting mTOR pathways., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Objective: De novo CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has different clinical characteristics compared with CD5-negative (CD5-) DLBCL. However, few studies have been reported in Chinese cohorts. We investigated the clinical features and prognosis of patients with CD5+ DLBCL and summarized the related literature., Methods: Data from 245 patients with newly diagnosed DLBCL were retrospectively assessed., Results: Thirty-one and 214 patients were diagnosed with CD5+ DLBCL or CD5- DLBCL, respectively. In the CD5+ DLBCL group, there were significantly higher proportions of patients with older age (≥60 years), International Prognostic Index (IPI) ≥3, Eastern Cooperative Oncology Group (ECOG) scores ≥ 2, bone marrow involvement, positive B-cell lymphoma 2 expression, and positive MYC expression. Survival analysis showed that CD5+ DLBCL had a markedly poorer 2-year progression-free survival than CD5- DLBCL (18.2% vs. 56.2%). Univariate analysis indicated that age ≥60 years, ECOG score ≥ 2, IPI ≥ 3, B symptoms, and no rituximab-based treatment were poor predictive factors for overall survival (OS). Multivariate analysis revealed that B symptoms and no rituximab-based treatment, but not positive CD5 expression, were independent factors for OS., Conclusions: Patients with CD5+ DLBCL had heterogeneous clinical characteristics and poor survival. The development of more targeted and effective therapies is needed.

Abstract: Primary cutaneous lymphoma occurring at the site of lymphedema is a rare complication. A total of 13 cases of primary cutaneous lymphoma associated with chronic lymphedema have been reported in international studies. We reported a case of cutaneous diffuse large B-cell lymphoma (DLBCL) (leg type) secondary to chronic lymphedema of the lower limbs. Histopathology showed hyperkeratosis of epidermis, acanthosis, and significant edema in the superficial dermis, with diffuse mononuclear infiltration in the dermis. Immunohistochemical studies revealed the expression of CD5, CD20, Pax-5, Bcl-2, Bcl-6, MUM-1, c-myc, and Ki-67. Therefore, the diagnosis of cutaneous DLBCL (leg type) was made. The study further confirmed the association between lymphoma and lymphedema. Especially, it showed CD5 expression. CD5-positive DLBCLs is a specific subgroup of DLBCLs, only approximately 10% of DLBCLs express CD5., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, and cell surface cluster of differentiation (CD) 5 expression may represent a distinct subset. Here, we provide a narrative review of CD5+ DLBCL to understand its clinical implications. Between 5-10% of DLBCL express CD5, making it an uncommon subset. Studies have variably shown that CD5+ DLBCL may be associated with increased age, high lactate dehydrogenase, B symptoms, extra-nodal sites, higher International Prognostic Index score, and advanced stage. CD5+ DLBCLs are more likely to express Bcl-2, MYC, and MUM1; a large proportion exhibit an activated B-cell (ABC)-like phenotype. The balance of studies generally supports an independent prognostic value of CD5 in DLBCL While more aggressive first-line regimens have been advocated for CD5+ DLBCL, including dose-adjusted R-EPOCH and autologous stem cell transplant, evidence to support these approaches is lacking; further study is warranted to identify the optimal treatment strategy for this disease entity.

Adoptive immunotherapy has emerged as a powerful approach to cure cancer and chronic infections. Currently, the generation of a massive number of T cells that provide long-lasting immunity is challenged by exhaustion and differentiation-associated senescence, which inevitably arise during in vitro cloning and expansion. To circumvent these problems, several studies have proposed an induced pluripotent stem cell (iPSC)-mediated rejuvenation strategy to revitalize the exhausted/senescent T cell clones. Because iPSC-derived cytotoxic T lymphocytes (iPSC-CTLs) generated via commonly used monolayer systems have unfavorable, innate-like features such as aberrant natural killer (NK) activity and limited replication potential, we modified the redifferentiation culture to generate CD8αβ + CD5 + CCR7 + CD45RA + CD56 - -adaptive iPSC-CTLs. The modified iPSC-CTLs exhibited early memory phenotype, including high replicative capacity and the ability to give rise to potent effector cells. In expansion culture with an optimized cytokine cocktail, iPSC-CTLs proliferated more than 10 15 -fold in a feeder-free condition. Our redifferentiation and expansion package of early memory iPSC-CTLs could supply memory and effector T cells for both autologous and allogeneic immunotherapies., Competing Interests: Declaration of interests S. Kaneko is a founder, shareholder, and chief scientific officer at Thyas Co., Ltd., and received research funding from Takeda Pharmaceutical Co., Ltd.; Kirin Co., Ltd.; Thyas Co., Ltd.; Astellas Co., Ltd.; Terumo Co., Ltd.; and Tosoh Co., Ltd., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Pretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients' immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4 + T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4 + T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4 + T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4 + T cell response. The depletion of the CD5 + B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10 + CD5 + B cells suppress the excessive response of anti-donor CD4 + T cells responses in sensitized recipients., (© 2021. The Author(s).)

Objectives: B-acute lymphoblastic leukemia (B-ALL) is a neoplasm of precursor lymphoid cells committed to the B-lineage. Expression of CD5 is rare in B-ALL., Methods: We studied the clinicopathologic, immunophenotypic, and molecular genetic features of 10 cases of B-ALL with aberrant CD5 expression, and compared with CD5-B-ALL., Results: B-ALL with aberrant CD5 expression is rare and predominantly affects men. Patients with CD5+ B-ALL had shorter median overall survival (21 vs 45 months, P = .0003). Expression of CD5 imposed a challenge in the differential diagnoses between B-ALL and other CD5+ B-cell lymphomas with blastic morphology. Dim CD20 and CD45, lack of surface immunoglobulin, expression of CD34 and TdT, negative immunostain for cyclin D1, and absence of t(11;14)(q13;q32) support a diagnosis of B-ALL., Conclusions: CD5 expression is rare in B-ALL and associated with poor clinical outcome. CD5+ B-ALL represents a distinct entity that needs to be considered in the differential diagnoses of CD5+ B-cell lymphoproliferative disorders., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a recently described kidney cancer entity with <60 published cases so far. Some unique features of BSARCC include distinct squamoid and alveolar morphology forming glomeruloid configurations and 2 types of tumor cells with different immunoprofiles. Although the mechanism is unknown, neutrophils and cellular materials engulfed by larger tumor cells (described as "emperipolesis") are observed in all reported cases including the current one. In this article, we report a case of a 70-year-old man who presented with an incidental renal mass during workup for immunoglobulin M monoclonal gammopathy of unknown significance and cold agglutinin autoimmune hemolytic anemia. A detailed pathologic evaluation and immunohistochemical studies revealed BSARCC colliding with atypical CD5+ monoclonal B-cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naïve CD4 + T cells. Further, we describe a relationship between CD5 levels on naïve human CD4 + T cells and binding affinity to foreign peptide, in addition to a predominance of CD5 hi T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5 lo and CD5 hi naïve human CD4 + T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naïve CD4 + T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

The effect of UV-light (240-390 nm) in doses of 151 and 755 J/m 2 on the expression of membrane markers CD5, CD19, CD20 in human peripheral blood B cells was studied by flow cytometry. In 24 h after exposure to UV light, we observed activation of processes accompanied by structural rearrangements of B-cell membranes leading to changes in the expression of receptor molecules: the content of of CD19 and CD20 increased due to activation of the synthesis of these proteins, while the content of CD5 decreased. The percentage of CD5 + cells decreased over 24 h after UV-irradiation of lymphocytes, while addition of autologous plasma to the incubation medium produced a photoprotective effect on CD5 + cells.

We encountered two cases of CD5 - blastoid variant mantle cell lymphoma (MCL), prompting us to investigate the proportion of CD5 negativity in MCL and assess the diagnosis of aggressive MCL variants. Among 117 patients diagnosed with MCL, CD5 negativity was observed in 13% (13/104) of cases with classical MCL and 15% (2/13) of cases with blastoid/pleomorphic variant MCL. Of the aggressive MCL variant cases, tumor cells exhibited intermediate nuclear size and required differential diagnosis between blastoid variant and classical MCL in six patients, and classical MCL cells were found in the background of aggressive variant tumors or in other sites in six patients. Of 1534 patients with diffuse large B-cell lymphoma (DLBCL), CD5 positivity was observed in 8% (121/1534) of cases. Immunohistochemical staining for cyclin D1 performed for these cases revealed one cyclin D1-positive and IGH/CCND1 fusion-positive case (0.9%, 1/114), namely pleomorphic variant MCL. Of the remaining 1413 patients initially diagnosed with CD5 - DLBCL, the diagnoses of two patients (0.1%) were amended to CD5 - blastoid variant MCL in the relapse phase based on morphology, cyclin D1 immunostaining, and fluorescence in situ hybridization. The incidence of CD5 negativity was similar between classical MCL and two aggressive variants. Accurate diagnosis of MCL variants was enabled by identifying a classical MCL component and/or CD5 positivity; however, we misdiagnosed two cases of CD5 - blastoid variant MCL. A small number of MCL variants may be included in CD5 - DLBCL cases. The diagnosis of CD5 - aggressive variant MCL remains challenging but crucial because of its therapeutic significance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Xenobiotic-mediated activation of the aryl hydrocarbon receptor (AHR) is immunotoxic in a number of immune cell types, with the B cell being a well-established sensitive target. Recent advances have provided evidence that the B cell repertoire is a heterogeneous population, with subpopulations exhibiting vastly different cellular and functional phenotypes. Recent work from our laboratory identified the T cell specific kinase lck as being differentially regulated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent activator of AHR. While LCK is primarily expressed in T cells, a subset of CD5 + B cells also express LCK. CD5 positivity describes a broad class of B lymphocytes termed innate-like B cells (ILBs) that are critical mediators of innate immunity through constitutive secretion of polyvalent natural immunoglobulin M (IgM). We hypothesized that CD5 + ILBs may be sensitive to AHR-mediated immunotoxicity. Indeed, when CD5 + B cells were isolated from the CD19 + pool and treated with TCDD, they showed increased suppression of the CD40 ligand-induced IgM response compared to CD5 - B cells. Further, characterization of the CD5 + population indicated increased basal expression of AHR , AHR repressor ( AHRR ), and cytochrome p450 family 1 member a1 ( CYP1A1 ). Indeed the levels of AHR-mediated suppression of the IgM response from individual donors strongly correlated with the percentage of the B cell pool that was CD5 + , suggesting that CD5 + B cells are more sensitive to AHR-mediated impairment. Together these data highlight the sensitive nature of CD5 + ILBs to AHR activation and provide insight into mechanisms associated with AHR activation in human B cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blevins, Zhou, Crawford and Kaminski.)

To investigate the phenotypic changes of the expression level of regulatory B cells and related molecules during the continuous infection of Echinococcus granulosus (E. granulosus) in mice and its relationship with E. granulosus infection and its immune effect. Experimental group mice were inoculated with protoscoleces suspension via intraperitoneally injection to prepare a mouse model of E. granulosus infection. Flow cytometry was used to detect the expression of regulatory B cells CD1d hi CD5 + CD19 hi cells and CD1d hi CD5 + CD19 hi IL-10 + cells in spleen and peripheral blood of mice. The expressions of IL-10 and TGF-β1 in mouse serum were detected via ELISA. The liver pathological changes in mice were observed by H&E staining; Moreover, the expressions and distribution of IL-10 and TGF-β1 in mice liver were measured through immunohistochemistry. The ELISA test results showed no significant changes in serum IL-10 and TGF-β1 levels in early infected mice. However, at the middle and late stages of infection, the levels of IL-10 and TGF-β1 in the serum of mice increased significantly (P < 0.05). The proportion of CD1d hi CD5 + CD19 hi Breg cells and the proportion of CD1d hi CD5 + CD19 hi IL-10 + Breg cells in the spleen of mice infected with E. granulosus were increased at 90 days after infection, which indicating that Breg cells proliferated in the late stage of infection. CD1d hi CD5 + CD19 hi regulatory B cells may be one of the causes of immunosuppression of E. granulosus infection. It is speculated that Bregs inhibitory effect may play a role by regulating the expression of cytokines and inducing the secretion of inhibitory cytokines IL-10 and TGF-β1.

A translocation involving the cyclin-dependent kinase 6 (CDK6) gene [t(CDK6)] is a rare but recurrent abnormality in B-cell neoplasms. To further characterise this aberration, we studied 57 cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T-cell receptor alpha locus (TRA)/T-cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B-cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus-associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy-chain variable-region (IGHV) locus sequencing revealed that none harboured an IGHV1-02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Innate-like CD5 + B1a cells localized in serous cavities are activated by innate stimuli, such as lipopolysaccharide (LPS), leading to T cell-independent antibody responses. Although ion channels play crucial roles in the homeostasis and activation of immune cells, the electrophysiological properties of B1a cells have not been investigated to date. Previously, in the mouse B cell lymphoma cells, we found that the voltage-independent two-pore-domain potassium (K2P) channels generate a negative membrane potential and drive Ca 2+ influx. Here, we newly compared the expression and activities of K2P channels in mouse splenic follicular B (FoB), marginal zone B (MZB), and peritoneal B1a cells. Next-generation sequencing analysis showed higher levels of transcripts for TREK-2 and TWIK-2 in B1a cells than those in FoB or MZB cells. Electrophysiological analysis, using patch clamp technique, revealed higher activity of TREK-2 with the characteristic large unitary conductance (~ 250 pS) in B1a than that in FoB or MZB cells. TREK-2 activity was further increased by LPS treatment (>2 h), which was more prominent in B1a than that in MZB or FoB cells. The cytosolic Ca 2+ concentration of B cells was decreased by high-K + -induced depolarization (ΔR KCl (%)), suggesting the basal Ca 2+ influx to be driven by negative membrane potential. The LPS treatment significantly increased the ΔR KCl (%) in B1a, though not in FoB and MZB cells. Our study was the first to compare the K2P channels in mouse primary B cell subsets, elucidating the functional upregulation of TREK-2 and augmentation of Ca 2+ influx by the stimulation of Toll-like receptor 4 in B1a cells.

Background: CD34 antigen is expressed by early hematopoietic progenitor cells and acute leukemia cells. Its expression is associated with good prognosis in acute myeloid leukemia. Literature is sparse on its prognostic significance in B- acute lymphoblastic leukemia (B-ALL) especially from India. Hence the present study was undertaken to analyse the frequency of CD34 expression in B-ALL in Indian patients and determine its prognostic significance by associating with other prognostic markers and aberrant antigen expression., Methods: Seventy-five B-ALL patients diagnosed by flow cytometry over a period of 3½ year were studied. Correlation of CD34 expression was studied with gender, age, total leucocyte count (TLC), French-American-British (FAB) morphological type, immuno-phenotypic markers, cytogenetics and minimal residual disease. Differences between groups were evaluated using Student's T-test for quantitative data and Chi-square test/Fishers exact T-test for qualitative variables. P value.

With the ever-increasing understanding of the roles of B cells in immune response and autoimmune pathogenesis, various techniques have been optimized for the detection of IL-10 production in B cells. In this chapter, we describe several commonly used methods for the effective detection of IL-10 in B cells at both mRNA and protein levels, including quantitative PCR analysis, intracellular staining of IL-10 in live B cells by flow cytometry, ELISA for secreted IL-10 detection, and ELISPOT assay for enumerating IL-10-producing B cells. We have further co-stained IL-10 with other cytokines and examined the staining efficiency. Moreover, we provide a detailed protocol for the detection of IL-10-producing B cells in situ by immunofluorescence microscopy. Since emerging evidence has suggested the promising strategy of cell therapy, we also provide a protocol to determine CD19 + CD1d hi CD5 + B-cell distribution upon adoptive transfer using tile-scan imaging. Together, the application of the described methods for the detection of IL-10 will facilitate the characterization of B-cell subsets with regulatory functions and enhance our current understanding of the critical roles of B cells in immune response and autoimmune development.

It is known that a subpopulation of T cells expresses two T cell receptor (TCR) clonotypes, though the extent and functional significance of this is not established. To definitively evaluate dual TCRα cells, we generated mice with green fluorescent protein and red fluorescent protein reporters linked to TCRα, revealing that ∼16% of T cells express dual TCRs, notably higher than prior estimates. Importantly, dual TCR expression has functional consequences, as dual TCR cells predominated response to lymphocytic choriomeningitis virus infection, comprising up to 60% of virus-specific CD4 + and CD8 + T cells during acute responses. Dual receptor expression selectively influenced immune memory, as postinfection memory CD4 + populations contained significantly increased frequencies of dual TCR cells. These data reveal a previously unappreciated contribution of dual TCR cells to the immune repertoire and highlight their potential effects on immune responses., Competing Interests: The authors declare no competing interest.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) accounts for approximately 1% of all lymphomas in our department. In this article, we describe the differential diagnosis of CLL/SLL from other indolent lymphomas, with special reference to follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and mantle cell lymphoma, although the latter is considered to be aggressive. CLL/SLL often exhibits proliferation centers, similar to follicular lymphoma. Immunohistological examination can easily distinguish these two lymphomas. The most important characteristic of CLL/SLL is CD5 and CD23 positivity. Mantle cell lymphoma is also CD5-positive and there are some CD23-positive cases. Such cases should be carefully distinguished from CLL/SLL. Some marginal zone lymphomas are also positive for CD5 and such cases are often disseminated. Lymphoplasmacytic lymphoma should also be a differential diagnosis for CLL/SLL. It frequently demonstrates MYD88 L265P, which is a key differential finding. By immunohistological examination, the expression of lymphoid enhancer-binding factor 1 is specific for CLL/SLL and can be a good marker in the differential diagnosis.

Despite its low frequency in all variants of diffuse large B-cell lymphoma (DLBCL), CD5 + DLBCL has gradually gained the attention it deserves, the result of its poorer outcomes compared to DLBCL without the CD5 signature. CD5 + DLBCL is classified as activated B-cell-like (ABC)/non-germinal-center B-cell-like (GCB) DLBCL with elusive genetic features, and patients are frequently characterized as being older and female, and as having Eastern Cooperative Oncology Group performance status > 1, high International Prognostic Index score, tendency to develop B symptoms, and advanced-stage disease with high central nervous system relapse and bone marrow involvement rate. The mechanism underlying the poor prognosis in CD5 + DLBCL has not been fully explored, and we summarize the reported potential mechanisms, including CD5-mediated B-cell receptor (BCR)-dependent and -independent pathways. The former involves the inhibition of BCR signaling, and the latter involves the BCR-independent overexpression of interleukin 10, Bcl-2 (antiapoptotic B-cell leukemia/lymphoma 2), cyclin D2, and CXCR4 (C-X-C motif chemokine receptor 4). The efficacy of traditional regimen R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently not satisfied in CD5 + DLBCL. Therapies of larger doses, such as R-DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab), R-ACVBP (rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), R-DA-EPOCH plus central nervous system prophylaxis, can improve the overall survival in CD5 + DLBCL patients, while allogeneic hematopoietic stem-cell transplantation still remains controversial as a salvage treatment. In addition, some novel drugs, such as lenalidomide, CXCR4 antagonists, Bruton tyrosine kinase inhibitors, Bcl-2 inhibitors, and immunotherapy, have been reported to have encouraging results and may improve the outcomes of these patients. In the present review, we comprehensively summarize the biology, mechanism, and treatment of CD5 + DLBCL., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The costimulatory molecule CD226 is highly expressed on effector/memory T cells and natural killer cells. Costimulatory signals received by T cells can impact both central and peripheral tolerance mechanisms. Genetic polymorphisms in CD226 have been associated with susceptibility to type 1 diabetes and other autoimmune diseases. We hypothesized that genetic deletion of Cd226 in the non-obese diabetic (NOD) mouse would impact type 1 diabetes incidence by altering T cell activation. CD226 knockout (KO) NOD mice displayed decreased disease incidence and insulitis in comparison to wild-type (WT) controls. Although female CD226 KO mice had similar levels of sialoadenitis as WT controls, male CD226 KO mice showed protection from dacryoadenitis. Moreover, CD226 KO T cells were less capable of adoptively transferring disease compared to WT NOD T cells. Of note, CD226 KO mice demonstrated increased CD8 + single positive (SP) thymocytes, leading to increased numbers of CD8 + T cells in the spleen. Decreased percentages of memory CD8 + CD44 + CD62L - T cells were observed in the pancreatic lymph nodes of CD226 KO mice. Intriguingly, CD8 + T cells in CD226 KO mice showed decreased islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-tetramer and CD5 staining, suggesting reduced T cell receptor affinity for this immunodominant antigen. These data support an important role for CD226 in type 1 diabetes development by modulating thymic T cell selection as well as impacting peripheral memory/effector CD8 + T cell activation and function., (Copyright © 2020 Shapiro, Yeh, Longfield, Gallagher, Infante, Wellford, Posgai, Atkinson, Campbell-Thompson, Lieberman, Serreze, Geurts, Chen and Brusko.)

Epidemiological studies of monoclonal B-cell lymphocytosis (MBL) have been conducted in limited geographical regions. Little is known about the prevalence of MBL in Asia. We investigated the prevalence and immunophenotypic characteristics of MBL in Koreans who had idiopathic lymphocytosis (lymphocyte count >4.0×109/L) and were ≥40 years of age. A total of 105 leftover peripheral blood samples met these criteria among those from 73,727 healthy individuals who visited the Health Promotion Center, Samsung Medical Center, Korea, from June 2018 to August 2019. The samples were analyzed using eight-color flow cytometry with the following monoclonal antibodies: CD45, CD5, CD10, CD19, CD20, CD23, and kappa and lambda light chains. The overall prevalence of MBL in the study population was 2.9% (3/105); there was one case of chronic lymphocytic leukemia (CLL)-like MBL (CD5+CD23+), one case of atypical CLL-like MBL (CD5+CD23-), and one case of CD5-MBL with a lambda restriction pattern. This is the first study on the MBL prevalence in an East Asian population, and it reveals a relatively low prevalence of MBL in healthy Korean individuals with lymphocytosis.

The precise detection of cancer cells currently remains a global challenge. One-dimensional (1D) semiconductor nanostructures (e.g., ZnO nanorods) have attracted attention due to their potential use in cancer biosensors. In the current study, it was demonstrated that the possibility of a photoluminescent detection of human leukemic T-cells by using a zinc oxide nanorods (ZnO NRs) platform. Monoclonal antibodies (MABs) anti-CD5 against a cluster of differentiation (CD) proteins on the pathologic cell surface have been used as a bioselective layer on the ZnO surface. The optimal concentration of the protein anti-CD5 to form an effective bioselective layer on the ZnO NRs surface was selected. The novel biosensing platforms based on glass/ZnO NRs/anti-CD5 were tested towards the human T-lymphoblast cell line MOLT-4 derived from patients with acute lymphoblastic leukemia. The control tests towards MOLT-4 cells were performed by using the glass/ZnO NRs/anti-IgG2a system as a negative control. It was shown that the photoluminescence signal of the glass/ZnO NRs/anti-CD5 system increased after adsorption of T-lymphoblast MOLT-4 cells on the biosensor surface. The increase in the ZnO NRs photoluminescence intensity correlated with the number of CD5-positive MOLT-4 cells in the investigated population (controlled by using flow cytometry). Perspectives of the developed ZnO platforms as an efficient cancer cell biosensor were discussed.

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5 hi ) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5 hi T cells expressed more of the NF-κB p65 protein than CD5 lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5 hi T cells over CD5 lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation., Competing Interests: The authors declare no competing interest.

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5 high and CD5 low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5 high and CD5 low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients ( n = 60) subgrouped according to the IgHV mutational status ( IgHV mut , n = 24; IgHV unmut , n = 36). CD5 high subpopulation showed a high percentage of CXCR3 ( P < 0.001), CCR10 ( P = 0.001), and CD62L ( P = 0.031) and high levels of CXCR5 ( P = 0.005), CCR7 ( P = 0.013) compared to CD5 low cells expressing high CXCR4 ( P < 0.001). Comparing IgHV mut and IgHV unmut patients, high levels of CXCR3 on CD5 high and CD5 low subpopulations were detected in the IgHV mut patients, with better discrimination in CD5 low subpopulation. Levels of CXCR3 on CD5 low subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5 high and CD5 low neoplastic cells in IgHV mut with a better prognosis compared to IgHV unmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Gayane Manukyan et al.)

CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes., Competing Interests: The authors declare no competing interest.

Background: Proliferation of large granular lymphocytes (LGL) and T-cell LGL (T-LGL) in peripheral blood along with demonstration of clonality are the hallmarks of a heterogeneous group of disorders, including T-LGL leukemia or T-LGL lymphocytosis. They are often associated with neutropenia and responsive to immunosuppression. The true nature of this entity is not well understood. Some cases are reported as reactive phenomena with very limited experience in pediatric population., Methods: Hematology/Oncology Flow Cytometry Laboratory database has been reviewed retrospectively. Patients with identifiable distinct CD5-dim T-cell population and positive clonal T-cell receptor rearrangement were included in the analysis. Clinical and laboratory data were then reviewed., Results: Sixteen cases of children and young adults with increased peripheral blood clonal T-LGL population characterized by dim CD5 expression with wide range of underlying immune dysregulation/stimulation disorders were reviewed. Extended follow up with repeat testing suggested the reactive nature of persistent clonal T-LGL proliferations in this group., Conclusions: Our observations indicate that clonal T-LGL proliferations in children and young adults are reactive in nature and some can be persistent with an indolent course with unknown consequentiality. Clonal T-LGL cells could be targeting the most prominent immunogenic stressor(s) involved as a control mechanism., (© 2020 Wiley Periodicals, Inc.)

Objectives: Lymphoid enhancer binding factor 1 (LEF1) is expressed in most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and has shown utility in distinguishing CLL/SLL from other small B-cell lymphomas. LEF1 expression has not been systematically studied in CD5-positive marginal zone lymphomas (MZLs), lymphoplasmacytic lymphomas (LPLs), and follicular lymphomas (FLs). We evaluated whether these cases lacked LEF1, helping to distinguish them from CLL/SLL., Methods: MZLs, LPLs, and FLs expressing CD5 were retrospectively studied for expression of LEF1 by immunohistochemistry., Results: LEF1 was absent in 17 of 18 CD5-positive lymphomas including 13 MZLs (2 nodal, 3 splenic, and 8 mucosa-associated lymphoid tissue lymphomas), 3 LPLs, and 1 of 2 FLs. One grade 3A CD5-positive FL expressed LEF1 in a majority of tumor cells., Conclusions: LEF1 is not expressed in most CD5-positive MZLs and LPLs; therefore, it is a reliable marker for distinguishing them from CLL/SLL. LEF1 may be expressed in CD5-positive FLs., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

T-cell malignancies often result in poor prognosis and outcome for patients. Immunotherapy has recently emerged as a revolutionary treatment against cancer, and the success seen in CD19 CAR clinical trials may extend to T cell diseases. However, a shared antigen pool coupled with the impact of T-cell depletion incurred by targeting T cell disease remain concepts to be clinically explored with caution. Here we report on the ability of T cells transduced with a CD5CAR to specifically and potently lyse malignant T-cell lines and primary tumors in vitro in addition to significantly improving in vivo control and survival of xenograft models of T-ALL. To extensively explore and investigate the biological properties of a CD5 CAR, we evaluated multiple CD5 CAR constructs and constructed 3 murine models to characterize the properties of CD5 down-regulation, the efficacy and specificity produced by different CD5 CAR construct designs, and the impact of incorporating a CD52 safety switch using CAMPATH to modulate the persistency and function of CAR cells. These data support the potential use of CD5CAR T cells in the treatment of T cell malignancies or refractory disease in clinical settings.