Carson Harrod (BIIR), Pascale Jeannin (Inserm U892), Maryna Eichelberger (FDA), and Gerard Zurawski (BIIR) for reading this manuscript. the different expression levels of pattern-recognition receptors within the APC subsets, microbial products do SIRT3 not bias them to elicit common types of immune reactions (Th1 or Th2). To evoke desired types of adaptive immune reactions in the human being vagina, antigens may need to become targeted to appropriate APC subsets with right adjuvants. lipopolysaccharide (LPS: TLR4 ligand), within the vaginal APC-induced CD4+ T cell reactions (Number 5b). R848 enhances LC- and CD14? LP-DC-induced CD4+ T cell proliferation (Supplementary Number 8a on-line), but decreases IL-5+CD4+ Dabigatran etexilate mesylate T cell reactions, as previously reported,33 without altering IFN+CD4+ T cell reactions. MDA5 was universally indicated in the four APC subsets, but the effect of poly IC was minimal except Dabigatran etexilate mesylate for the enhanced CD4+ T cell proliferation induced by CD14+ LP-DCs and M Supplementary Number 8a on-line). Flagellin enhanced CD4+ T cell proliferation induced from the four APC subsets. Interestingly, however, flagellin-activated CD14? LP-DCs decreased both IFN+CD4+ and IL-5+CD4+ T cell reactions, while flagellin-activated Menhanced both IFN+CD4+ and IL-5+CD4+ T cell reactions. Both poly IC and flagellin enhanced CD8+ T cell proliferation induced from the 4 APC subsets (Supplementary Number 8b on-line). However, poly IC did not significantly alter the levels of IFN+CD8+ or IL-5+CD8+ T cell reactions induced from the DC subsets, but enhanced M-induced IFN+CD8+ T cell reactions (Number 5c). TLR4 was highly indicated in M, but LPS did not significantly alter M-induced IFN+ or IL-5+ T cell reactions (Supplementary Number 9 on-line). It rather advertised LC- and CD14? LP-DC-induced CD4+ T cell proliferation (Supplementary Number 9a on-line) and LC- and CD14+ LP-DC-induced CD8+ T cell proliferation (Supplementary Number 9b on-line). Taken collectively, individual subsets of the vaginal APCs display their personal practical plasticity in directing CD4+ and CD8+ T cell responses. None of the stimuli bias the 4 APC subsets to induce common types of immune responses. Thus, the immune responses, particularly Th1 vs. Th2, in the vagina can be well balanced by distinct but compensatory functions of the individual APC subsets in the vagina. Both LCs and CD14? LP-DCs are potent inducers of IL-22-producing CD4+ T cells IL-22 induces the secretion of anti-microbial products and contributes to the recovery of epithelial cells.34-37 As shown in Figure 6a, both LCs and CD14? LP-DCs display comparable ability to induce IL-22+CD4+ T cell responses, although LCs in human skins are superior to dermal-DCs38. Data from 6 impartial experiments are summarized in Physique 6b. CD14? LP-DC-induced IL-22+CD4+ T cells were further analyzed for IFN, IL-17, and IL-5 expression (Physique 6c). Summarized data indicate that the overall quality of IL-22+CD4+ T cells induced with the 4 APC subsets is similar (Physique 6d), but different from those induced with the control IFNDCs. Compared to the vaginal APCs, IFNDCs induced less numbers of IL-22 single+ CD4+ T cells. Approximately 3-5% of the IL-22+CD4+ T cells induced with IFNDCs also expressed IL-17. It was also of note that approximately 40-60% of the IL-22+CD4+ T cells induced by the vaginal APCs expressed IFN. Although the 3 subsets of vaginal DCs resulted in greater IL-22+CD8+ T cell responses than did M in some experiments, there was no significant difference between the DCs and Mat inducing IL-22+CD8+ T cell responses Physique 6e). IL-22+CD8+ T cells induced with the APC subsets displayed comparable patterns of IL-5 and IFN expression, the majority of the IL-22+CD8+ T cells also expressed IFN or IL-5, but not IL-17 (Physique 6f). Open in a separate window Physique 6 Vaginal LCs and CD14? LP-DCs can efficiently induce IL-22-producing T cell responses. CFSE-labeled allogeneic na?ve total T cells were co-cultured for 7 days with the vaginal APCs or IFNDCs. T cells were restimulated with PMA/ionomycin in the presence of brefeldin A and then stained for intracellular IL-22. (a-d, g) Data for CD4+ Dabigatran etexilate mesylate T cells (e, f, h) Data for CD8+ T cells. (a) Representative data from one experiment are presented. (b, e) Summarized data from 6 impartial experiments (* indicates p 0.05; One-way ANOVA test). (c, d, f) Frequency of IFN+, IL-5+ and IL-17+ cells among the IL-22-producing T cells. 5 independent experiments using APCs from different donors showed similar results. (c) Representative data from one experiment after co-culture with CD14?.
Carson Harrod (BIIR), Pascale Jeannin (Inserm U892), Maryna Eichelberger (FDA), and Gerard Zurawski (BIIR) for reading this manuscript