Differential effects of IL-2 and IL-15 on the death and survival of activated TCRγδ⁺ intestinal intraepithelial lymphocytes

TCRγδ⁺ cells are enriched in the intestine mucosa and constitute approximately half of the intestinal intraepithelial lymphocytes (iIEL) in mice. They are likely activated by self and foreign Ags in situ, but little is known about how the activated γδ iIEL are regulated. In the iIEL compartment, IL-2 is produced by activated TCRαβ⁺ iIEL, and IL-15 message is detected in iIEL, and in the epithelial cells. We found surface expression of IL-2 as well as IL-15Rs on activated γδ iIEL, and examined the effects of IL-2 and IL-15 on the survival and death of γδ iIEL during secondary stimulation through TCR. We found that both cytokines supported growth of the restimulated γδ iIEL, but exerted different effects on their survival. A significant higher number of live cells were recovered from the γδ iIEL cultures restimulated in IL-15 than in IL-2. Quantitation of apoptotic cells showed more cell death in the IL-2 group than in the IL-15 group. The cell death was associated with restimulation through TCR and was not caused by insufficient growth factor, thus representing activation-induced cell death. Western blot analyses found no difference in the levels of Bcl-2 and Bax proteins between the two groups. However, the level of Bcl-x(L) protein diminished with time in the IL-2 group whereas the level was sustained in the IL-15 group, which may contribute to the pro-survival effect of IL-15. These results demonstrated that the survival of activated γδ iIEL is differentially regulated by IL-2 and IL-15.