介白素 15 調控腸道介白素 17A 及干擾素-γ的產生

Abstract

Interleukin-15 (IL-15) is essential for the development and survival of several lineages of lymphocyte and is expressed by many cell types, including intestinal epithelial cell (IEC). To understand the function of IL-15 in the intestinal immune system, I used Il15f/f Vil-Cre mice generated in our lab to investigate the function of IEC-derived IL-15. I found that, unlike Il15-/- mice, Il15f/f Vil-Cre mice had no deficiency of NK cells, NKT cells and TCRβ+CD8+ T cells in the intestine lamina propria (LP) or in non-intestinal lymphoid organs, but showed similar level of reduction of TCRγδ+NK1.1-CD8+ cells in the small intestine LP (siLP) as Il15-/- mice. Therefore, IEC-derived IL-15 was likely sufficient to support for the homeostasis of TCRγδ+NK1.1-CD8+ siLP cells. For intestinal intraepithelial lymphocytes (iIELs), Il15-/- mice showed reduction in the CD8αα single positive (SP, CD4-CD8+) and CD4+CD8- (double negative, DN) subsets of TCRβ+ and TCRγδ+ iIELs in the small intestine and colon, and reduction of CD8αβ SP subset of TCRβ+ and TCRγδ+ siIELs. IEC-derived IL-15 was sufficient to support the homeostasis of TCRβ+CD8αα SP siIELs and cIELs, and the homeostasis of TCRγδ+ CD8αα SP and CD8αβ SP siIELs. Whereas IEC-derived IL-15 partially supported the homeostasis of TCRβ+ DN cIELs and of TCRγδ+ DN siIELs and cIELs but did not support the homeostasis of TCRβ+CD8αβ SP and TCRβ+DN siIELs, and TCRγδ+ CD8αα SP cIELs. Interleukin-17 (IL-17) and interferon-γ (IFN-γ) are critical for mucosal defense and epithelial barrier function in the intestine, respectively. The regulation of intestinal IL-17 and IFN-γ production is not fully understood. I found that Il15-/- mice displayed elevated IL-17A+ cell frequency in TCRβ+ and TCRγδ+ DN cells of the siLP and colon LP (cLP), and in TCRβ+CD4+ cells of the siLP; whereas, Il15f/f Vil-Cre mice displayed elevated IL-17A+ cell frequency in TCRβ+ DN and CD4+ cells of the siLP. However, IL-15 does not affect IL-17A production by iIELs. Thus, IL-15 negatively regulates intestinal IL-17A production by TCRβ+ and TCRγδ+ DN cells in the siLP and cLP, and TCRβ+ CD4+ cells in the siLP. I also found that IL-15 regulates intestinal IFN-γ production. In the LP, Il15-/- mice showed decreased IFN-γ+ cells in TCRγδ+DN siLP and cLP cells and in TCRβ+DN siLP cells, but increased IFN-γ+ cells in TCRβ+ CD4+ and CD8+ cLP cells. On the other hand, IEC-derived IL-15 positively regulated IFN-γ production in TCRγδ+DN siLP cells. In the IEL compartment, Il15-/- mice had increased IFN-γ+ cells in TCRβ+CD8αα SP and DN siIELs and cIELs, in TCRβ+CD4+CD8+ (double positive, DP) siIELs, and in TCRβ+CD8αβ SP cIELs, but decreased IFN-γ+ cells in TCRγδ+DN siIELs. On the other hand, Il15f/f Vil-Cre mice had increased IFN-γ+ cells in TCRβ+CD8αα SP siIEL and TCRβ+CD8αβ+ cIEL, but decreased IFN-γ+ cells in TCRγδ+DN siIELs. Thus, IL-15 negatively regulates intestinal IFN-γ production by TCRβ+CD8αα SP and DN iIELs and by TCRβ+CD8αβ SP cIELs, while positively regulates IFN-γ production by TCRγδ+DN siIELs. In addition to cytokine production, I also found that Il15-/- mice had reduced regulatory T cells (Treg) cells in the siLP. However, IL-15 is not essential for induction of oral tolerance. Taken together, this study reveals the regulation of intestinal IL-17A and IFN-γ production by IL-15.