IL-15 is a multi-functional cytokine widely expressed with its private high affinity receptor α chain (IL-15Rα). Together they form a complex in the ER and exist in transmembrane and soluble forms. Based on bone marrow chimera studies on IL-15–affected lymphocyte homeostasis, it is generally thought that the membrane-bound IL-15–IL-15Rα complex signals through IL-15Rβγ on neighboring lymphocytes, a mechanism termed trans presentation. IL-15 also signals through IL-15Rα alone in myeloid cells. We have studied function of the IL-15 system in lymphocyte development and function.
T cell central tolerance removes excessive autoreactivity from newly developed T cells in the thymus. We found that IL-15Rα is preferentially expressed in the thymus medulla. Il-15-/- and Il-15ra-/- mice are normal in the development of naturally occurring Treg, while display reduced negative selection of T cell receptor autoreactivity. This function of IL-15 and IL-15Rα requires their expression by thymic antigen presentation cells. Consistently, CD4+ T cells developed in the knockout mice showed elevated autoreactivity. Moreover, aged Il-15-/- and Il-15ra-/- mice develop a late-onset autoimmune phenotype that resembles Sjogren's syndrome. Therefore, IL-15 represents a new layer of regulation in T cell-mediated autoimmunity. We are dissecting the molecular mechanism of how IL-15 system affects thymocyte negative selection.
Several types of cells in the intestine express IL-15 and IL-15Rα, such as intestinal epithelial cell (IEC) and lamina propria (LP) dendritic cell (DC) and monocyte. The IL-15 system of IEC is essential for the maintenance and development of CD8αα+ intestinal intraepithelial lymphocytes (iIELs), IEC IL-15 thusmay affect local immunity via affecting the iIEL or cells in the LP. We have delineated how IL-15 promotes the survival of CD8αα+ iIELs, and we are studying the effect of several IL-15 sources on the intestinal immune response to food antigens.