IL-15 Promotes Survival But Not Effector Function Differentiation of CD8+ TCRαβ+ Intestinal Intraepithelial Lymphocytes

Abstract

CD8 single-positive cells, including CD8αα+ and CD8αβ+ subsets, constitute the majority of TCRαβ+ intestinal intraepithelial lymphocytes (αβ iIEL) in mice. CD8+ αβ iIEL show significantly weaker responses to TCR stimulation in the presence of exogenous IL-2 than do CD8+ T cells of the central immune system. IL-15 is a T cell growth factor likely expressed in the intestine mucosa. To understand the role of IL-15 in CD8+ αβ iIEL biology, we compared the effects of exogenous IL-15 and IL-2 on the survival and primary responses of the two CD8+ αβ iIEL subsets in vitro. In contrast to the death of ∼60% of both CD8αα+ and CD8αβ+ iIEL cultured in IL-2 with or without TCR stimulation, IL-15 promoted survival of the CD8αα+ subset in the presence of TCR stimulation and promoted survival of both subsets in the absence of TCR stimulation. The higher proliferation level of TCR stimulated CD8αα+ αβ iIEL cultured in IL-15 compared with those cultured in IL-2 is likely due to IL-15’s prosurvival effects. In addition, unlike exogenous IL-2, exogenous IL-15 did not support the effector functions of either iIEL subsets, including IFN-γ production, IL-4-induced Th2 cytokine production, and anti-TCR mAb-redirected cytotoxicity. These findings demonstrate that IL-15 and IL-2 are functionally distinct and suggest that IL-15 plays a unique role in the maintenance of the CD8+ αβ iIEL pool in the absence of Ag stimulation and in the survival and expansion of CD8αα+ αβ iIEL upon Ag stimulation.