CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function
Ian LewkowichNancy HermanKathleen W. SchleiferMatthew P. DanceBrian L. ChenKrista DiengerAlyssa SprolesJaimin S. ShahJörg KöhlYasmine BelkaidMarsha Wills‐Karp
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Abstract:
The role of natural CD4+CD25+ regulatory T (T reg) cells in the control of allergic asthma remains poorly understood. We explore the impact of T reg cell depletion on the allergic response in mice susceptible (A/J) or comparatively resistant (C3H) to the development of allergen-induced airway hyperresponsiveness (AHR). In C3H mice, anti-CD25-mediated T reg cell depletion before house dust mite treatment increased several features of the allergic diathesis (AHR, eosinophilia, and IgE), which was concomitant with elevated T helper type 2 (Th2) cytokine production. In similarly T reg cell-depleted A/J mice, we observed a moderate increase in airway eosinophilia but no effects on AHR, IgE levels, or Th2 cytokine synthesis. As our experiments suggested that T reg cell depletion in C3H mice before sensitization was sufficient to enhance the allergic phenotype, we characterized dendritic cells (DCs) in T reg cell-depleted C3H mice. T reg cell-depleted mice had increased numbers of pulmonary myeloid DCs with elevated expression of major histocompatibility complex class II, CD80, and CD86. Moreover, DCs from T reg cell-depleted mice demonstrated an increased capacity to stimulate T cell proliferation and Th2 cytokine production, which was concomitant with reduced IL-12 expression. These data suggest that resistance to allergen-driven AHR is mediated in part by CD4+CD25+ T reg cell suppression of DC activation and that the absence of this regulatory pathway contributes to susceptibility.Keywords:
CD80
CD86
T helper cell
SUMMARY Dendritic cells (DCs) were prepared from human bronchoalveolar lavage (BAL) cells. We previously reported that, in particular, the CD1a fraction of the low autofluorescent (LAF) cells contains the precursors for DCs: after overnight culture, 40% of the LAF cells change into functionally and phenotypically prototypic dendritic/veiled cells. There are, as yet, no data on the modulatory effects of glucocorticoids (GC) on the maturation and function of such DCs isolated from the human lung. Functional tests (allogeneic mixed lymphocyte reaction: allo-MLR) were therefore performed with CD1a+ LAF cells at different stimulator-to-T-cell ratios and after preincubation with different dexamethasone (DEX) concentrations. DEX caused suppression of the T-cell stimulatory capacity of CD1a+ LAF cells, which was dose-dependent, and more evident at the higher stimulator-to-T-cell ratios. Here, we also show that CD80 and CD86 are normally expressed at low levels on CD1a+ LAF cell-derived DCs compared to other DC populations. This low-level expression of costimulatory molecules is discussed here in relation to the previously reported low-level expression of CD80 (and CD86) on lung DCs in experimental animals. This appears to play a role in a predominant Th2 cell stimulating potential of DC from the lung environment. DEX exposure of CD1a+ LAF cells prevented the upregulation of even this low-level expression of CD80 and CD86. The veiled/dendritic morphology and the expression of other relevant cell surface markers and adhesion molecules was not affected by DEX exposure. It is concluded that DEX hampers the maturation of CD1a+ LAF cells into active lung DCs.
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Abstract Alcohol consumption inhibits accessory cell function and Ag-specific T cell responses. Myeloid dendritic cells (DCs) coordinate innate immune responses and T cell activation. In this report, we found that in vivo moderate alcohol intake (0.8 g/kg of body weight) in normal volunteers inhibited DC allostimulatory capacity. Furthermore, in vitro alcohol treatment during DC differentiation significantly reduced allostimulatory activity in a MLR using naive CD4+ T cells, and inhibited tetanus toxoid Ag presentation by DCs. Alcohol-treated DCs showed reduced IL-12, increased IL-10 production, and a decrease in expression of the costimulatory molecules CD80 and CD86. Addition of exogenous IL-12 and IL-2, but not neutralization of IL-10, during MLR ameliorated the reduced allostimulatory capacity of alcohol-treated DCs. Naive CD4+ T cells primed with alcohol-treated DCs showed decreased IFN-γ production that was restored by exogenous IL-12, indicating inhibition of Th1 responses. Furthermore, CD4+ T cells primed with alcohol-treated DCs were hyporesponsive to subsequent stimulation with the same donor-derived normal DCs, suggesting the ability of alcohol-treated DCs to induce T cell anergy. LPS-induced maturation of alcohol-treated immature DCs partially restored the reduced allostimulatory activity, whereas alcohol given only during DC maturation failed to inhibit DC functions, suggesting that alcohol primarily impairs DC differentiation rather than maturation. NFκB activation, a marker of DC maturation was not affected by alcohol. Taken together, alcohol both in vitro and in vivo can impair generation of Th1 immune responses via inhibition of DC differentiation and accessory cell function through mechanisms that involve decreased IL-12 induction.
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Objective : This study was carried out for the purpose of knowing the effect from T-cell activation of the C57BLh mouse by the extraction from a EGRR. Methods : CD80, CD86, CD28, CTW-4 is the most imporbnt costimulatory molecules. CD80 and CD86 molecules are expressed on activated antigen-presenting cells(APCs) and bind to their ligands CD28 and CTLA-4 on T cells. Natural CD4 CD25+ T cells may be candidates as a major regulatory T-cell subset. Indeed, CD4 CDE+ T cells were shown to control autoreactive T cells. CD44 mediates leukocyte activation and CD69 acts as a costimulatory molecule for T cell activation and proliferation. So we investigated the effects of EGRR on cell surface antigens(CD25, CD28, CD44, CD69, CD80) expressed by T cells following activation. Results : 1. In order to know the effect of the cytotoxicity from extraction of EGRR, we had to examine the safe density of that on lung fibroblast cells of the mouse(mLFCs). EGRR did not show cytotoxicity against mLFCs. 2. In the prolifeous effect of thymus T cells, water extracts of GRR played an important role on the proliferating thymus T cells compared with control group. 3. EGRR up-regulates CD44'CD69'CD25', CD4'CD25', CD8'CIY25'. CD3'CD80' expression but not CD3'CDB' by anti -CD3- stimulated T cells. Conclusions : -4bove results indicates that EGRR play an important role in the activation of autoreactive T cells by up-regulating cell surface molecule(CD80, CD25, CD44). Therefore further deep stucfies shoud be accomplished about its mechanisms.
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CD28 and CTLA-4 are opposing regulators of T cell activation, triggered by the two ligands CD80 and CD86. How these ligands promote either T cell activation via CD28 or inhibition via CTLA-4 is not understood. Using CD80 and CD86 molecules expressed on transfected cells, we have identified a major difference between these ligands in that CD80 transfectants have the ability to inhibit activation of resting human peripheral blood T cells via interaction with CTLA-4, whereas CD86 transfectants do not. Rather, CTLA-4-CD86 interactions appear to contribute towards T cell proliferation. We also observed that CTLA-4 function is strongly influenced by TCR stimulation, effects being observed only at relatively low levels of TCR stimulation. The kinetics of CD80-CTLA-4 interactions revealed that CTLA-4 inhibition took place within the first 8 h of T cell stimulation, despite there being little measurable CTLA-4 expression on the majority T cells. However, significant amounts of CTLA-4 were observed in the CD25(+) CD4(+) subset of T cells which, when removed from the cultures, accounted for the CTLA-4 inhibition observed. Overall, these data provide evidence that CD80 and CD86 differ in their interactions with CTLA-4 and that CD80 appears to be the preferential inhibitory ligand for CTLA-4 working via a population of CD4(+) CD25(+) CTLA-4(+) regulatory T cells.
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Abstract This study evaluated the contribution of the inhibitory molecule B7 homolog-1 (B7-H1) to the regulation of alloimmune responses by pDC. mPDCA-1+ splenic pDC from wild type (WT) or B7-H1 knockout (KO) mice were pulsed with donor antigen (Ag). Cell phenotype was analyzed for Ag-presenting and co-regulatory molecules and T cell allostimulatory capacity was assessed in mixed leukocyte reaction (MLR). WT or KO pDC pulsed with donor Ag were injected into syngeneic mice and CD4+ T cells were purified 7 days later for secondary MLR. T cell proliferation was assessed by 3H-thymidine incorporation and cytokines quantified by ELISA. BALB/c hearts were transplanted into untreated C57BL/6 controls or into mice receiving syngeneic pDC pulsed with donor Ag 7 days before grafting. pDC expressed low levels of CD40, CD80, CD86, MHC I/II, and B7-H1 and showed poor CD4+ T cell stimulatory capacity compared to conventional myeloid DC. pDC from KO mice exhibited greater T cell stimulatory capacity compared to WT controls. T cells from mice given immature, donor Ag-pulsed KO pDC showed greater proliferation and secreted more IFN-γ in secondary MLR compared to WT controls. Recipient-derived, immature WT pDC pulsed with donor Ag prolong allograft survival. These results reveal that B7-H1 on pDC contributes to regulation of alloreactive T cell responses. This work was funded by the transplantation immunology training grant NIAID T32 AI 074490.
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Mixed lymphocyte reaction
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