The latter event facilitated the dissociation of Bim from Bcl-2 without affecting Bim abundance in IL-15-treated CD8αα+ iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl-2 or removal

of Bim from CD8αα+ iIELs promoted their survival in Il15ra−/− mice. Taken together, IL-15 promotes CD8αα+ iIEL survival by both increasing Bcl-2 levels and dissociating Bim from Lapatinib Bcl-2 through activation of a Jak3-Jak1-PI3K-Akt-ERK1/2 pathway, which differs from a previously reported IL-15-induced survival signal. Intestinal intraepithelial lymphocytes (iIELs) are T cells located between the epithelial cells lining the intestinal lumen. In the small intestine of C57BL/6J (B6J) mice, approximately half the iIELs are conventional T cells, while the other half are CD4−CD8β−CD8α+ (CD8αα+) cells that consist of 30% TCRαβ+ (αβ) cells and 70% TCRγδ+ NSC 683864 clinical trial (γδ) cells. CD8αα+ iIELs are developmentally and functionally distinct from conventional T cells. Most CD8αα+ iIEL precursors go through a thymic stage of development, and complete maturation in the intestine [1-4]. Functionally, CD8αα+ iIELs

appear to assume an immune regulatory role in the gut mucosa, as implied by their production of immune suppressive cytokines, such as TGF-β and IL-10, and by their ability to inhibit colitis [5, 6]. IL-15 is a pleiotropic cytokine widely expressed with its exclusive high affinity receptor IL-15Rα, while IL-15Rβγ chains are the intermediate affinity receptors for both IL-15 and IL-2 and expressed mainly by hematopoietic cells [7-9]. IL-15 and IL-15Rα form a complex during synthesis

in the ER and exist as transmembrane and soluble forms [10]. Afatinib in vivo The transmembrane IL-15–IL-15Rα complex is “in trans presented” to the IL-15Rβγ on neighboring cells for usage [11]. This mode of IL-15 usage has been implied to control the homeostasis of several lymphoid lineages, including CD8αα+ iIELs [1, 12-14]. More than 90% of CD8αα+ iIELs are missing in Il15−/− [15], Il15ra−/− [16], and Il15rb−/− [17] mice. Bone marrow chimera studies indicate that parenchymal IL-15Rα is essential for the development and maintenance of CD8αα+ αβ and γδ iIELs in the intestine [2, 14]. IL-15 also sustains the survival of primary CD8αα+ αβ and γδ iIELs in vitro [2, 18, 19]. As specific expression of IL-15Rα in the intestinal epithelial cell (IEC) of Il15ra−/− mice restores CD8αα+ iIELs and their Bcl-2 level [1], Bcl-2 has been implicated in the prosurvival effect of the IL-15 system. However, overexpression of Bcl-2 only moderately restored CD8αα+ γδ iIELs in Il15−/− mice [20], suggesting that the increase in the level of Bcl-2 alone is not sufficient to account for the prosurvival effect of IL-15.