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BackgroundThe early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8TN), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (

Background: The early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8TN), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)). Methods: The ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models. Results: At the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8TN percentages (medians: 48.7% vs. 31.0%, P = 0.001), and a marginally higher CD4TN (61.2% vs. 53.1%, P = 0.33). In adolescents, early ART was associated with low CD4TN percentages and less differentiated memory CD8 T cells. CD4TN and CD8TN levels were inversely related to cellular activation and gut permeability. Conclusion: In children and adolescents, the benefits of early ART for CD8TN were clear after long-term ART. The impact of early ART on CD4TN appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the de novo production of TN cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on TN levels. Clinical Trial Registration: ClinicalTrials.gov , identifier NCT02674867. [ABSTRACT FROM AUTHOR]

Previously we reported that the sensitivity of CD4+ T cells to ATP does not depend on P2X7 receptor (P2X7R) expression levels but on their activation and differentiation stages. Therefore, here we have investigated a potential relationship between the sensitivity of CD8+ T cells to ATP and their stages of differentiation. Thus, the CD8+ subpopulation exhibits a drastically reduced sensitivity to ATP with aging, which parallels the strong increase of an effector/memory CD8+ subset expressing high levels of CD44 cell adhesion molecule and CD45RB transmembrane phosphatase (CD44hiCD45RBhi). Using l-selectin/CD62L, CC-chemokine receptor 7, and CD127/IL-7 receptor-a markers, we showed that effector/memory CD8+ T cells belong to a central or effector memory subset. In contrast, the CD44hiCD45RBhi effector/memory subset is absent or poorly expressed in the CD4+ T subpopulation regardless of age. While ATP treatment can trigger channel and pore formation, CD62L shedding, phosphatidylserine exposure, and cell death in the CD44loCD45RBhi-naive CD8+ subset, it is unable to induce these cellular activities in the CD44hiCD45RBhi effector/memory CD8+ subset. Importantly, both CD44loCD45RBhi-naive and CD44hiCD45RBhi effector/memory subsets express similar low levels of P2X7R, demonstrating that the sensitivity of CD8+ T cells to ATP depends on the stage of differentiation instead of P2X7R expression levels. [ABSTRACT FROM AUTHOR]

The thymus plays an important role in the development of the immune cell pool; it serves as the primary location for T-lymphocyte maturation. Early cardiac surgical interventions for congenital heart defects are necessarily associated with thymectomy, i.e. the partial or complete removal of the thymus. A newborn infant already has a functioning thymus and developed cells of the immune system. However, thymectomy eliminates the primary location where T cells differentiate and mature. This study summarizes the current knowledge of the cellular disturbances and potential clinical consequences associated with performing thymectomy in children treated surgically for congenital heart defects. [ABSTRACT FROM AUTHOR]

In youths infected with human immunodeficiency virus (HIV) during the perinatal period, naive CD4 and recent thymic emigrant CD4 percentages were positively correlated with both CD4 T-cell count and past and current HIV replication, demonstrating the persistence of high-level thymic activity in long-term infection.Background. Children born at the start of the human immunodeficiency virus (HIV) epidemic and infected during the perinatal period are now young adults living with the virus. Naive T-lymphocyte restoration is essential for the maintenance of a diverse T-cell receptor repertoire and for immunity to pathogens.Methods. The ANRS-EP38-IMMIP study included 93 patients infected with HIV type 1 (HIV-1) during the perinatal period. Naive CD4 (CD4N) and CD8 (CD8N) T lymphocytes and CD4 recent thymic emigrants (CD4RTE) were quantified in the peripheral blood by flow cytometry. Wilcoxon tests, Pearson correlation coefficients, and linear regressions were used to study their associations with HIV disease parameters.Results. Median CD4N, CD8N, and CD4RTE percentages were 56% (interquartile range [IQR], 44–64), 31% (IQR, 22–44), and 79% (IQR, 74–83), respectively. The three T-lymphocyte subsets were positively correlated with CD4 T-cell count. Patients aviremic at the time of the study tended to have a lower CD4N percentage (55% vs 58%; P = .10), a significantly higher CD8N percentage (39% vs 22%; P < .0001), and a significantly lower CD4RTE percentage (77% vs 81%; P = .003) than viremic patients. In aviremic patients, CD4N percentages were positively associated with cumulative viremia over the last 10 years (r = 0.335; P = .01) and were significantly higher in patients harboring X4R5 viruses than in those harboring R5 viruses (61% vs 44%; P = .001).Conclusions. After at least 15 years of HIV infection, perinatally infected youths had preserved CD4N and CD4RTE levels. This persistence of high levels of thymic activity potentially compensating for the deleterious effects of current and past HIV replication is remarkable. [ABSTRACT FROM PUBLISHER]

Human CD93 has a molecular weight of about 100 kDa and is selectively expressed by myeloid cell lineages in peripheral blood (PB) mononuclear cells. Although CD93 was initially identified as a receptor for complement component 1, subcomponent q phagocytosis (C1qRp) involved in the C1q-mediated enhancement of the phagocytosis of various antigens, several recent studies have reported that CD93 is not a receptor for the C1q-mediated enhancement of phagocytosis. The expression patterns of CD93 have been previously investigated in PB mononuclear cells (lymphocytes, monocytes, and granulocytes) from adult PB and neonatal umbilical cord blood (UCB), and the expression of CD93 was not found on lymphocytes from either normal adult PB or neonatal UCB. However, the detection of CD93 expression in neonatal UCB using CD93 monoclonal antibodies (mAbs) that recognize different antigenic epitopes remains poorly understood. In this study, we examined the expression of CD93 on lymphocytes, monocytes, and granulocytes from neonatal UCB using four different types of CD93 mAb detection probes, mNI-11, R139, R3, and X-2, using flow cytometric and western blot analyses. We found that CD93, as defined using all four mAbs, was expressed on monocytes and granulocytes in PB mononuclear cells from adult PB and neonatal UCB. On the other hand, we observed for the first time that the expression of CD93 on lymphocytes in neonatal UCB can only be detected using the mNI-11 mAb, established in our laboratory, and not with commercially available CD93 mAbs (R139, R3, and X-2). However, CD93 expression on lymphocytes from normal adults was not detected using any of the four CD93 mAbs. Two-color flow cytometric analyses showed that the CD93 recognized by mNI-11 mAb was expressed on CD3 T lymphocytes (mainly CD4 helper T lymphocytes), but not on CD19 B lymphocytes or on CD8 suppressor/cytotoxic T lymphocytes from neonatal UCB. In addition, CD93 was expressed on CD45RA (naive antigen) lymphocytes from neonatal UCB, but not on CD45RO (memory antigen) lymphocytes from neonatal UCB or on CD45RA and CD45RO lymphocytes from normal adult PB. Three-color flow cytometric analysis showed that CD93 was co-expressed on naive T lymphocytes (CD4CD45RA) from neonatal UCB. In a western blot analysis, the CD93 mAb (mNI-11) immunoprecipitated at a molecular weight of 98 kDa, identified as a CD93 molecule, in the CD4CD45RA cells from neonatal UCB but not from adult PB, similar to the results in the human monocyte-like cell line U937 (human CD93-positive cells). Taken together, these results provide the first direct evidence of a novel/naive cell population (CD4CD45RACD93) in neonatal UCB that may have an important role in cell biology, transplantation, and immature/mature immune responses. [ABSTRACT FROM AUTHOR]

Abstract: After the provision of highly active antiretroviral therapy (HAART), the level of circulating CD4+ T cells increases in many adults infected with the human immunodeficiency virus, type 1 (HIV). To study factors involved in immune reconstitution, we have measured thymic abundance by CT scans, circulating naïve-phenotype CD4+ T cells by flow cytometry, and T cell receptor (TCR) rearrangement excision circles (TRECs) by quantitative PCR in 40 virologically suppressed, HIV-infected adults and 33 age-matched, HIV-uninfected controls. In HIV-uninfected subjects, naïve T cell numbers, thymic abundance, and the frequency of circulating naïve CD4+ T cells bearing TRECs decreased with age, as expected. When corrected for this relationship with age, naïve T cell numbers correlated significantly with naïve T cell TREC frequencies. Virologically suppressed HIV-infected subjects had higher TREC frequencies, and subjects over the age of 39 were more likely to have abundant thymus compared to age-matched, HIV-uninfected adults. Nevertheless, all HIV-infected subjects had reduced absolute numbers of naïve T cells, irrespective of thymic size, age, or TREC frequencies. These data illustrate the complex relationship between these measures of thymic size and function and underscore the need to develop more definitive measures of thymic function in the future. [Copyright &y& Elsevier]

Summary. In chronic myelogenous leukaemia (CML), clonal change occurs in all myeloid and B-cell lineages, but very rarely T-cell lineages. A detailed three-colour cytometric analysis of peripheral lymphocytes was performed in 22 patients with chronic-phase CML (CP-CML). CD45 gating analysis was used to discriminate between lymphocytes and basophils. The peripheral lymphocyte pool was comprised of a significant proportion of naive CD4 cells, defined by a CD4+ 45RA+ phenotype [47·0 ± 19·6% (mean ± SD) of the total CD4+ cells], and naive CD8 cells, defined by a CD8+ CD45RA+ CD28+ phenotype (35·1 ± 19·7% of total CD8+ cells), even in patients with long disease duration. The percentage of CD8 naive T cells showed inverse correlation with age, whereas no correlation was observed with disease duration. Possible explanations for the preservation of naive lymphocytes include (1) that the naive T cells differentiated from co-existing normal stem cells or (2) that long-lived naive T cells persisted from the CML onset and expanded peripherally (thymus independent). Either mechanism or a combination of both mechanisms might contribute to maintaining the naive compartment size. [ABSTRACT FROM AUTHOR]

Previously we reported that the sensitivity of CD4 + T cells to ATP does not depend on P2X 7 receptor (P2X 7 R) expression levels but on their activation and differentiation stages. Therefore, here we have investigated a potential relationship between the sensitivity of CD8 + T cells to ATP and their stages of differentiation. Thus, the CD8 + subpopulation exhibits a drastically reduced sensitivity to ATP with aging, which parallels the strong increase of an effector/memory CD8 + subset expressing high levels of CD44 cell adhesion molecule and CD45RB transmembrane phosphatase (CD44 hi CD45RB hi ). Using l-selectin/CD62L, CC-chemokine receptor 7, and CD127/IL-7 receptor-α markers, we showed that effector/memory CD8 + T cells belong to a central or effector memory subset. In contrast, the CD44 hi CD45RB hi effector/memory subset is absent or poorly expressed in the CD4 + T subpopulation regardless of age. While ATP treatment can trigger channel and pore formation, CD62L shedding, phosphatidylserine exposure, and cell death in the CD44 lo CD45RB hi -naive CD8 + subset, it is unable to induce these cellular activities in the CD44 hi CD45RB hi effector/memory CD8 + subset. Importantly, both CD44 lo CD45RB hi -naive and CD44 hi CD45RB hi effector/memory subsets express similar low levels of P2X 7 R, demonstrating that the sensitivity of CD8 + T cells to ATP depends on the stage of differentiation instead of P2X 7 R expression levels.-Mellouk, A., Bobé, P. CD8 + , but not CD4 + effector/memory T cells, express the CD44 high CD45RB high phenotype with aging, which displays reduced expression levels of P2X 7 receptor and ATP-induced cellular responses.

High endothelial venules (HEVs) are structurally distinct blood vessels that develop during embryonic and neonatal life in all secondary lymphoid organs except the spleen. HEVs are critical for initiating and maintaining immune responses because they extract naïve and memory lymphocytes from the bloodstream, regardless of antigen receptor specificity, and deliver them to antigen-presenting cells inside lymph nodes under homeostatic conditions. HEVs also develop postnatally in nonlymphoid organs during chronic inflammation driven by autoimmunity, infection, allografts, and cancer. Extranodal HEVs are usually surrounded by dense lymphocytic infiltrates organized into lymph-node like, T- and B-cell-rich areas called tertiary lymphoid structures (TLS). HEV neogenesis is thought to facilitate the generation of tissue-destroying lymphocytes inside chronically inflamed tissues and cancers.We are studying the mechanisms underpinning HEV neogenesis in solid cancers and the role of homeostatic T-cell trafficking in controlling cancer immunity. In this chapter we describe methods for identifying HEV in tissue sections of cancerous tissues in humans and mice using immunohistochemical staining for the HEV-specific marker peripheral lymph node addressin (PNAd). L-selectin binding to PNAd is a necessary first step in homeostatic lymphocyte trafficking which is the defining function of HEV. We also describe methods to measure L-selectin-dependent homing of lymphocytes from the bloodstream into lymphoid tissues and tumors in preclinical cancer models.