Lineage relationships, homeostasis, and recall capacities of central– and effector–memory CD8 T cells in vivo

The lineage relationships of central–memory T cells (TCM) cells and effector–memory T cells (TEM), as well as their homeostasis and recall capacities, are still controversial. We investigated these issues in a murine model using two complementary approaches: T cell receptor repertoire analysis and adoptive transfer experiments of purified H-Y–specific TCM and TEM populations. Repertoire studies showed that approximately two thirds of TCM and TEM clones derived from a common naive precursor, whereas the other third was distinct. Both approaches highlighted that TCM and TEM had drastically distinct behaviors in vivo, both in the absence of antigen or upon restimulation. TCM clones were stable in the absence of restimulation and mounted a potent and sustained recall response upon secondary challenge, giving rise to both TCM and TEM, although only a fraction of TCM generated TEM. In contrast, TEM persisted for only a short time in the absence of antigen and, although a fraction of them were able to express CD62L, they were unable to mount a proliferative response upon secondary challenge in this model

Association between Thymic Function and Allogeneic Hematopoietic Stem Cell Transplantation Outcome: Results of a Pediatric Study

Abstract Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities

High prevalence of low affinity peptide–MHC II tetramer–negative effectors during polyclonal CD4+ T cell responses

Two-dimensional analysis reveals that peptide–MHC class II tetramers underestimate the frequency of cytokine-producing antigen-specific CD4+ T cells in polyclonal responses

Enhancement of Tumour-Specific Immune Responses In Vivo by ‘MHC Loading-Enhancer’ (MLE)

BACKGROUND:Class II MHC molecules (MHC II) are cell surface receptors displaying short protein fragments for the surveillance by CD4+ T cells. Antigens therefore have to be loaded onto this receptor in order to induce productive immune responses. On the cell surface, most MHC II molecules are either occupied by ligands or their binding cleft has been blocked by the acquisition of a non-receptive state. Direct loading with antigens, as required during peptide vaccinations, is therefore hindered. PRINCIPAL FINDINGS:Here we show, that the in vivo response of CD4+ T cells can be improved, when the antigens are administered together with 'MHC-loading enhancer' (MLE). MLE are small catalytic compounds able to open up the MHC binding site by triggering ligand-release and stabilizing the receptive state. Their enhancing effect on the immune response was demonstrated here with an antigen from the influenza virus and tumour associated antigens (TAA) derived from the NY-ESO-1 protein. The application of these antigens in combination with adamantane ethanol (AdEtOH), an MLE compound active on human HLA-DR molecules, significantly increased the frequency of antigen-specific CD4+ T cells in mice transgenic for the human MHC II molecule. Notably, the effect was evident only with the MLE-susceptible HLA-DR molecule and not with murine MHC II molecules non-susceptible for the catalytic effect of the MLE. CONCLUSION:MLE can specifically increase the potency of a vaccine by facilitating the efficient transfer of the antigen onto the MHC molecule. They may therefore open a new way to improve vaccination efficacy and tumour-immunotherapy

Altered T Cell Memory and Effector Cell Development in Chronic Lymphatic Filarial Infection That Is Independent of Persistent Parasite Antigen

Chronic lymphatic filarial (LF) infection is associated with suppression of parasite-specific T cell responses that persist even following elimination of infection. While several mechanisms have been implicated in mediating this T cell specific downregulation, a role for alterations in the homeostasis of T effector and memory cell populations has not been explored. Using multiparameter flow cytometry, we investigated the role of persistent filarial infection on the maintenance of T cell memory in patients from the filarial-endemic Cook Islands. Compared to filarial-uninfected endemic normals (EN), microfilaria (mf) positive infected patients (Inf) had a reduced CD4 central memory (TCM) compartment. In addition, Inf patients tended to have more effector memory cells (TEM) and fewer effector cells (TEFF) than did ENs giving significantly smaller TEFF ∶ TEM ratios. These contracted TCM and TEFF populations were still evident in patients previously mf+ who had cleared their infection (CLInf). Moreover, the density of IL-7Rα, necessary for T memory cell maintenance (but decreased in T effector cells), was significantly higher on memory cells of Inf and CLInf patients, although there was no evidence for decreased IL-7 or increased soluble IL7-Rα, both possible mechanisms for signaling defects in memory cells. However, effector cells that were present in Inf and CLInf patients had lower percentages of HLA-DR suggesting impaired function. These changes in T cell populations appear to reflect chronicity of infection, as filarial-infected children, despite the presence of active infection, did not show alterations in the frequencies of these T cell phenotypes. These data indicate that filarial-infected patients have contracted TCM compartments and a defect in effector cell development, defects that persist even following clearance of infection. The fact that these global changes in memory and effector cell compartments do not yet occur in infected children makes early treatment of LF even more crucial

MerTK regulates thymic selection of autoreactive T cells

T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) are believed to be the result in part of inefficient negative selection of self-specific thymocytes. However, the events regulating thymic negative selection are not fully understood. In the current study, we demonstrate that nonobese diabetic (NOD) mice lacking expression of the Mer tyrosine kinase (MerTK) have reduced inflammation of the pancreatic islets and fail to develop diabetes. Furthermore, NOD mice deficient in MerTK expression (Mer−/−) exhibit a reduced frequency of β cell-specific T cells independent of immunoregulatory effectors. The establishment of bone marrow chimeric mice demonstrated that the block in β cell autoimmunity required hematopoietic-derived cells lacking MerTK expression. Notably, fetal thymic organ cultures and self-peptide administration showed increased thymic negative selection in Mer−/− mice. Finally, thymic dendritic cells (DC) prepared from Mer−/− mice exhibited an increased capacity to induce thymocyte apoptosis in a peptide-specific manner in vitro. These findings provide evidence for a unique mechanism involving MerTK-mediated regulation of thymocyte negative selection and thymic DC, and suggest a role for MerTK in contributing to β cell autoimmunity

Etude des lymphocytes T de mémoire centrale (Tcm) et effectrice (Tem) chez l'homme et chez la souris (voies de différenciation, homéostasie et capacités de réponse secondaire)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Pathways of memory CD8+ T-cell development.

CD8(+) T-cell responses must have at least two components, a replicative cell type that proliferates in the secondary lymphoid tissue and that is responsible for clonal expansion, and cytotoxic cells with effector functions that mediate the resolution of the infection in the peripheral tissues. To confer memory, the response must also generate replication-competent T cells that persist in the absence of antigen after the primary infection is cleared. The current models of memory differentiation differ in regards to whether or not memory CD8(+) T cells acquire effector functions during their development. In this review we discuss the existing models for memory development and the consequences that the recent finding that memory CD8(+) T cells may express granzyme B during their development has for them. We propose that memory CD8(+) T cells represent a self-renewing population of T cells that may acquire effector functions but that do not lose the naïve-like attributes of lymphoid homing, antigen-independent persistence or the capacity for self-renewal