Modulation of cytokine responses of murine CD8+ αβ 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+ TCRαβ+ intestinal intraepithelial lymphocyte (αβ ilEL) 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-γ by the CD8αβ+ αβ ilEL significantly but only marginally affected the CD8αα+ subset, whereas IL-4 induced IL-4, IL- 5, and IL-10 production and augmented TGF-β production by both subsets. CD28 costimulation induced production of Th2 cytokines by CD4+ ilEL in the absence of exogenous IL-4. Unlike lymph node CD4+ cells, the CD28 costimulation- induced Th2 differentiation of CD4+ ilEL was not inhibited by IFNγ. These results demonstrate active cytokine production by CD4+, CD8αβ+, as well as CD8αα+αβ ilEL. The Th2-skewed cytokine profile of CD8αα+αβ ilEL and the IFNγ-resistance of Th2 differentiation of the CD4+αβ ilEL suggest that both ilEL subsets contribute to the induction of noninflammatory mucosal immune responses.