210 research outputs found
Ex-vivo expanded DC induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin allografts
No full textDendritic cells (DCs) are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide-major histocompatibility complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T-cell development, induction of T-cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs, obtained from bone marrow cultured with either Flt3L (FLDCs) or granulocyte-macrophage colony-stimulating factor (GMDCs), could induce allospecific central and peripheral tolerance after IV injection; B cells were used as a control. The results showed that only FLDCs reached the thymus after injection and that these cells induced both central and peripheral tolerance to donor major histocompatibility complexes. For central tolerance, injection of FLDCs induced antigen-specific clonal deletion of both CD8 and CD4 single-positive thymocytes. For peripheral tolerance, injection of FLDCs induced donor-specific T-cell unresponsiveness and prolonged survival of donor-derived skin grafts. Tolerance induction by adoptive transfer of FLDCs could be a useful approach for promoting graft acceptance after organ transplantation. (Blood. 2011; 117(9): 2640-2648)11Nsciescopu
Unique Features of Naive CD8+ T Cell Activation by IL-2
No full textIL-2 has a pervasive influence on the immune system and dictates the survival and differentiation of multiple T cell subsets, including
CD4 regulatory T cells, CD4 Th cells, and CD8 memory cells. IL-2 is synthesized by T cells during the early stages of the
immune response and promotes T cell expansion and effector cell generation after initial activation via TCR signaling. Based on
studies with activated T cell lines maintained in vitro, IL-2 is known to activate multiple signaling pathways that show considerable
overlap with the pathways elicited via the TCR. In this paper, we have examined IL-2 signaling under TCR-independent conditions,
namely by culturing purified resting naive CD8 T cells with IL-2 in the absence of Ag or APC. Under these conditions, we show in
this study that IL-2 elicits a unique pattern of signaling associated with strong lymphocyte-specific protein tyrosine kinase/JAK3-
dependent activation of the PI3K/AKT pathway with little or no involvement of STAT5, NF-kB, or the calcineurin/NFAT pathways.
Such signaling induces marked proliferation associated with rapid and selective expression of eomesodermin but not T-bet and
differentiation into long-lived central memory cells after adoptive transfer. The Journal of Immunology, 2013, 191: 5559–5573.116171sciescopu
Interleukin-21 Is Critically Required in Autoimmune and Allogeneic Responses to Islet Tissue in Murine Models
No full textOBJECTIVE-Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. RESEARCH DESIGN AND METHODS-NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed. RESULTS-Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. CONCLUSIONS-Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes. Diabetes 60:867-875, 20111151sciescopu
CD45-mediated control of TCR tuning in naïve and memory CD8+ T cells
No full textContinuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8+ T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8+ T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8+ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens
The majority of murine gamma delta T cells at the maternal-fetal interface in pregnancy produce IL-17
No full textData source: Supplementary information, http://www.nature.com.access.library.unisa.edu.au/icb/journal/v94/n7/suppinfo/icb201648s1.htmlCompared with lymphoid tissues, the immune cell compartment at mucosal sites is enriched with T cells bearing the γδ T-cell receptor (TCR). The female reproductive tract, along with the placenta and uterine decidua during pregnancy, are populated by γδ T cells predominantly expressing the invariant Vγ6(+)Vδ1(+) receptor. Surprisingly little is understood about the function of these cells. We found that the majority of γδ T cells in the non-pregnant uterus, pregnant uterus, decidua and placenta of mice express the transcription factor RORγt and produce interleukin-17 (IL-17). In contrast, IFNγ-producing γδ T cells were markedly reduced in gestational tissues compared with uterine-draining lymph nodes and spleen. Both uterine-resident invariant Vγ6(+) and Vγ4(+) γδ T cells which are more typically found in lymphoid tissues and circulating blood, were found to express IL-17. Vγ4(+) γδ T cells were particularly enriched in the placenta, suggesting a pregnancy-specific recruitment or expansion of these cells. A small increase in IL-17-producing γδ T cells was observed in allogeneic compared with syngeneic pregnancy, suggesting a contribution to regulating the maternal response to paternally-derived alloantigens. However, their high proportions also in non-pregnant uteri and gestational tissues of syngeneic pregnancy imply a role in the prevention of intrauterine infection or quality control of fetal development. These data suggest the need for a more rigorous evaluation of the role of IL-17 in sustaining normal pregnancy, particularly as emerging data points to a pathogenic role for IL-17 in pre-eclampsia, pre-term birth, miscarriage and maternal immune activation-induced behavioral abnormalities in offspring.Gabriela V Pinget, Theresa M Corpuz, Jessica Stolp, Erin L Lousberg, Kerrilyn R Diener, Sarah A Robertson, Jonathan Sprent and Kylie E Webste
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