Presence or Absence of TGF-β Determines IL-4-Induced Generation of Type 1 or Type 2 CD8 T Cell Subsets

Abstract

CD8+ T cells often differentiate into highly cytotoxic cells, secreting a Th1-like or type 1 cytokine pattern characterized by the production of IFN-γ. However, cytotoxic, and in some reports, noncytotoxic, type 2 cells that secrete IL-4, IL-5, or IL-10 instead of IFN-γ, can be generated when CD8+ T cells are primed in the presence of IL-4. Here, we show that IL-4 can also generate typical CD8 type 1 responses. Indeed, while presence of TGF-β biases the development of CD8 T cells that, then, produce little cytolytic activity and IFN-γ, addition of IL-4 results in the recovery of cytotoxicity and IFN-γ production. The cooperative effects of TGF-β and IL-4 imply dual functions, not only for IL-4, but also for TGF-β. Indeed, depending on the presence or absence of IL-4, TGF-β either inhibits or induces the generation of type 1 CD8+ T cells. Physiologically, the ratio of local IL-4/TGF-β concentration may therefore be a critical element in determining the outcome of T cell responses to pathogen and autoantigens. It allows CD8 T cells to switch from an immunotolerant state in the presence of only TGF-β or IL-4, to an immunocompetent proinflammatory type 1 state in the absence or presence of both cytokines.