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Rheumatoid arthritis (RA) is an autoimmune disease, associated with chronic inflammation and the imbalance of Th17/Treg. Stanniocalcin‐1 (STC‐1), a glycoprotein, was found to have anti‐inflammatory, anti‐oxidative stress and anti‐apoptosis properties. The present study aimed to investigate the immunomodulatory effect of STC‐1 and its potential value in the treatment of RA. Here, a mouse model of collagen‐induced arthritis (CIA) was established. Then body weight, joint erythema and swelling were measured in CIA mice with or without STC‐1 treatment. Haematoxylin and eosin (H and E) staining was performed to determine histopathological change. Moreover, the percentage of Th17 and Treg cells in the spleen and inguinal lymph nodes (ILNs) and the culture supernatant in polarizing conditions were examined by flow cytometry. Cytokines in serum were detected by ELISA. As a result, the arthritis score, histologic inflammation and cartilage destruction were decreased in CIA mice treated with STC‐1. STC‐1 increased the level of transforming growth factor‐β and inhibited the expression of interleukin‐17. In CIA mice, the percentage of CD4+IL‐17A+ cells in the spleen and ILNs were decreased after STC‐1 treatment, while the level of CD4+Foxp3+ cells did not change significantly. In vitro, STC‐1 inhibited Th17 cell differentiation and STAT3 phosphorylation in CD4+ T cells under Th17 cell‐polarizing conditions. Collectively, the results demonstrated that STC‐1 alleviated RA by inhibiting Th17 cell differentiation through regulating STAT3 phosphorylation. STC‐1 may be a potential drug for the treatment of RA. [ABSTRACT FROM AUTHOR]

Autoreactive T cells with the phenotype and function of different memory subsets are present in patients who developed type 1 diabetes (TID). According to the progressive differentiation model, memory subsets generate from naïve precursors in a linear and unidirectional path depending on the strength and quality of stimulatory signals. By observing human naïve T cells in contact with GAD65 loaded autologous dendritic cells, we observed that approximately 10% of cells divided with the plane of cell division parallel to the one of the immune synapse, causing phenotypic asymmetries in the proximal and distal daughter T cells. After the first T cell division, proximal and distal daughter T cells showed different phenotype, metabolic signature and commitment to differentiate towards long‐lived memory T cells or T cells with effector function. Subjects with or without T1D showed a similar frequency of asymmetric T cell division (ATCD) for autoantigens and recall antigens specific T cells, however the frequency of ATCD is significantly increased in autoreactive T cells in patients with T1D when IL‐7 was added to the culture. An increased upregulation of GLUT1 in response to IL‐7 in patients with T1D was related to the rate of ATCD. Our results showed that ATCD is associated with an early divergence in the differentiation fate of naïve T cells specific for GAD65 during first antigen encounter. [ABSTRACT FROM AUTHOR]

There are two approaches to scientific investigation, the common approach (proving one's theory) and Popper's approach (falsification of one's theories). Popper's approach has advantages as well as dangers (being perceived as not sure of one's theories, or even be hostile to them—an 'auto‐traitor'). Nevertheless, the Popper approach can bridge the gap between inhibition (directly observable) and inhibitory regulation (not directly observable). Suppression of immune responses by antigen‐specific antibody has led to theories regarding immunoregulation by immune products. There are many immune products capable of regulating immune responses. The inhibitory outcomes of this regulation have been called coinhibition and immune checkpoint inhibition. Coinhibition should be used when regulation begins at the cell surface or in the cell cytoplasm, which opens up the possibility of antigen‐specific regulation. Immune checkpoint inhibition should be used when the initiating inhibitory event occurs in the nucleus, such as by directly affecting the cell cycle, where the concept of antigen‐specific regulation is more difficult to invoke. These forms of immunoregulation could be corrupted by viral infections, such as in COVID‐19 infections. [ABSTRACT FROM AUTHOR]

Introduction: The frequencies and functions of T stem cell memory (TSCM) subsets vary in autoimmune diseases. We evaluated the frequencies of CD4+ and CD8+ TSCM subsets as well as their PD‐1 expression levels in patients with T1D. Methods: Blood samples were collected from new case (NC) (n = 15), and long‐term (LT) (n = 15) groups and healthy controls (n = 15). Five subsets of T cells including TCM(CD4+/CD8+ CCR7+ CD45RO+ CD95+), TCMhi (CD4+/CD8+ CCR7+ CD45ROhi CD95+), TEM(CD4+/CD8+ CCR7− CD45RO+ CD95+), TSCM(CD4+/CD8+ CCR7+ CD45RO− CD95+), and T naive (CD4+/CD8+ CCR7+ CD45RO− CD95−) were detected by flow‐cytometry. Results: The frequency of CD4+ TSCM was higher in NC patients than LT patients and controls (p <.0001 and p =.0086, respectively). A higher percentage of the CD8+ T naive cells was shown in NC patients as compared with LT and healthy individuals (p =.0003 and p =.0002, respectively). An increased level of PD‐1 expression was observed on the CD4+TCM and TCMhi cells in LT patients as compared with healthy controls (p =.0037 and p =.0145, respectively). Also, the higher PD‐1 expression was observed on the CD8+ TCM and TCMhi in NC and LT patients as compared with controls (p =.0068 and p <.0001; p =.0012 and p =.0012, respectively). Conclusion: Considering TSCMs' capacities to generate all memory and effector T cells, our results may suggest a potential association between the increased frequencies of TSCMs and T1D progression. [ABSTRACT FROM AUTHOR]

CD4+FOXP3+ Tregs are currently explored to develop cell therapies against immune‐mediated disorders, with an increasing focus on antigen receptor‐engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG‐3 and CTLA‐4 in LNs, while IL‐10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL‐10, CTLA‐4, and LAG‐3 were nonredundantly required for the protective function of antigen receptor‐engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg‐derived IL‐10 and CTLA‐4 were both required to suppress acute autoreactive CD4+ T‐cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor‐engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks. [ABSTRACT FROM AUTHOR]

The contribution of low‐affinity T cells to autoimmunity in the context of polyclonal T‐cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a result, low‐affinity T cells are often disregarded as nonantigen‐specific cells irrelevant to the immune response. Our study aimed to assess how the level of self‐antigen reactivity shapes T‐cell lineage and effector responses in the context of spontaneous tissue‐specific autoimmunity observed in NOD mice. Using multicolor flow cytometry in combination with Nur77GFP reporter of TCR signaling, we identified a dormant population of T cells that infiltrated the pancreatic islets of prediabetic NOD mice, which exhibited reduced levels of self‐tissue reactivity based on expression of CD5 and Nur77GFP. We showed that these CD5low T cells had a unique TCR repertoire and exhibited low activation and minimal effector function; however, induced rapid diabetes upon transfer. The CD4+CD5low T‐cell population displayed transcriptional signature of central memory T cells, consistent with the ability to acquire effector function post‐transfer. Transcriptional profile of CD5low T cells was similar to T cells expressing a low‐affinity TCR, indicating TCR affinity to be an important factor in shaping CD5low T‐cell phenotype and function at the tissue site. Overall, our study suggests that autoimmune tissue can maintain a reservoir of undifferentiated central memory‐like autoreactive T cells with pathogenic effector potential that might be an important source for effector T cells during long‐term chronic autoimmunity. [ABSTRACT FROM AUTHOR]

The importance of the negative selection of self‐reacting cells from immune repertoires was easily recognized since it would militate against autoimmune disease. However, while the existence of positive selection in the auditioning of newly formed immune cells is now recognized, it is taking longer to understand its role. With the removal or suppression by negative selection of a subset of immune cells that self‐react, would the specificities of remaining immune cells range widely to confront the universe of 'non‐self' antigens, including some borne by potential microbial pathogens? Alternatively, from among those remaining immune cells, could some be picked out (positively selected) based on 'advanced knowledge' of some character likely to be common to those pathogens? To exploit 'holes' created by negative selection, it was predicted that pathogens would attempt to mimic their hosts by progressive stepwise mutation towards host 'self'—a process entailing passage through a host anti‐'near‐self‐reactivity' arena. Anticipating this, those hosts that over evolutionary time 'learned' to positively select from developing immune repertoires, cells with reactivities against 'near‐self', would be advantaged by natural selection. The benefits of this narrowing of the range of host immune reactivities are now clearer and may solve Burnet's paradox, which concerns the ability of an organism's immune cells to attack its own cancer cells. However, while supporting this in the context of T cell immunity, Manczinger and his colleagues now suggest that some wily pathogens may be exploiting their hosts' narrow defence foci by 'seeking', through mutation, dissimilarity from host 'self'. [ABSTRACT FROM AUTHOR]

The pathogenic immune response in celiac disease (CeD) is orchestrated by phenotypically distinct CD4+ T cells that recognize gluten epitopes in the context of disease‐associated HLA‐DQ allotypes. Cells with the same distinct phenotype, but with elusive specificities, are increased across multiple autoimmune conditions. Here, whether sorting of T cells based on their distinct phenotype (Tphe cells) yields gluten‐reactive cells in CeD is tested. The method′s efficiency is benchmarked by parallel isolation of gluten‐reactive T cells (Ttet cells), using HLA‐DQ:gluten peptide tetramers. From gut biopsies of 12 untreated HLA‐DQ2.5+ CeD patients, Ttet+/Tphe+, Ttet−/Tphe+, and Ttet−/Tphe− cells are sorted for single‐cell T‐cell receptor (TCR)‐sequencing (n = 8) and T‐cell clone (TCC)‐generation (n = 5). The generated TCCs are TCR sequenced and tested for their reactivity against deamidated gluten. Gluten‐reactivity is observed in 91.2% of Ttet+/Tphe+ TCCs, 65.3% of Ttet−/Tphe+ TCCs and 0% of Ttet−/Tphe− TCCs. TCR sequencing reveals clonal expansion and sequence sharing across patients, features reflecting antigen‐driven responses. The feasibility to isolate antigen‐specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease‐driving CD4+ T cells in autoimmune conditions. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. In addition to anti‐platelet autoantibodies, CD8+ T cells have been implicated as a mechanism of platelet destruction. The current evidence for the existence of platelet‐specific CD8+ T cells in ITP is inconclusive. The purpose of this review is to summarize the studies that investigated CD8+ T cells in ITP and to review the methods that have been used to detect autoreactive CD8+ T cells in other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Oral lichen planus (OLP) is a T cell–mediated immunoinflammatory disease. Glycolysis plays an essential role in T‐cell immune responses. Blocking glycolytic pathway in activated T cells represents a therapeutic strategy for restraint of immunologic process in autoimmune disorders. 2‐Deoxy‐D‐glucose (2‐DG) has been widely used to probe into glycolysis in immune cells. This study was aimed to explore the role of glycolysis inhibition by 2‐DG on regulating immune responses of OLP‐derived T cells. We observed that lactic dehydrogenase A (LDHA) expression was elevated in OLP lesions and local T cells. 2‐DG inhibited the expression of LDHA, p‐mTOR, Hif1α and PLD2 in T cells; meanwhile, it decreased proliferation and increased apoptosis of T cells. T cells treated by 2‐DG showed lower LDHA expression and elevated apoptosis, resulting in a reduced apoptotic population of keratinocytes that were co‐cultured with them, which was related to the decreased levels of IFN‐γ in co‐culture system. Rapamycin enhanced the effects of 2‐DG on immune responses between T cells and keratinocytes. Thus, these findings indicated that OLP‐derived T cells might be highly dependent upon high glycolysis for proliferation, and 2‐DG treatment combined with rapamycin might be an option to alleviate T‐cell responses, contributing to reducing apoptosis of keratinocytes. [ABSTRACT FROM AUTHOR]