Modulation of cytokine responses of murine CD8+ alphabeta intestinal intraepithelial lymphocytes by IL-4 and IL-12

The immune responses of the intestine mucosa feature the noninflammatory type, such as IgA production and oral tolerance. Th2 type cytokines have been implicated in the induction of these noninflammatory responses. In the present study, cytokine responses of CD8+ and CD4+ TCRalphabeta+ intestinal intraepithelial lymphocyte (alphabeta iIEL) subsets to TCR stimulation under the influence of IL-12, IL-4, or CD28 costimulation were examined. IL-12 enhanced production of IL-10 and IFN-gamma by the CD8alphabeta+ alphabeta iIEL significantly but only marginally affected the CD8alphaalpha+ subset, whereas IL-4 induced IL-4, IL-5, and IL-10 production and augmented TGF-beta production by both subsets. CD28 costimulation induced production of Th2 cytokines by CD4+ iIEL in the absence of exogenous IL-4. Unlike lymph node CD4+ cells, the CD28 costimulation-induced Th2 differentiation of CD4+ iIEL was not inhibited by IFN-gamma. These results demonstrate active cytokine production by CD4+, CD8alphabeta+, as well as CD8alphaalpha+ alphabeta iIEL. The Th2- skewed cytokine profile of CD8alphaalpha+ alphabeta iIEL and the IFN-gamma-resistance of Th2 differentiation of the CD4+ alphabeta iIEL suggest that both iIEL subsets contribute to the induction of noninflammatory mucosal immune responses.