Early Th1/Th2 cell polarization in the absence of IL-4 and IL-12: T cell receptor signaling regulates the response to cytokines in CD4 and CD8 T cells

Differentiation of developing T cells into the type 1 (IFN-gamma -producing ) or type 2 (IL-4-producing) subsets is a central theme of immune regulatio n. The balance of IL-4 and IL-12 present during T cell activation has been considered the major influence on type 1 versus type 2 development. Here we show that CD4 T cells can become biased towards type 1 or type 2 phenotype s during their initial activation in the absence of IL-4 or IL-12. This typ e of regulation is dependent on the balance of MAPkinase, protein kinase C, and calcineurin signaling after TCR engagement. Later maturation of Th1 or Th2 effecters is dependent on IL-12 or IL-4. However Tc1 CD8 effector deve lopment is independent of IL-12, and Tc2 cell generation requires both appr opriate TCR signals and IL-4 early in effector development. Using an altere d peptide ligand to stimulate TCR transgenic T cells, we show that altered signaling regulates the numbers of CD8 cells capable of developing into Tc2 effecters, and also their responsiveness to IL-4. Together, the results su pport a two-stage model of differentiation in which intermediate cells bias ed towards the type 1 or type 2 pathways after activation, are subsequently matured in response to IL-12 or IL-4, respectively.