A critical role for interleukin 4 in activating alloreactive CD4 T cells.

To generate antigen-specific responses, T cells and antigen presenting cells (APCs) must physically associate with each other and elaborate soluble factors that drive the full differentiation of each cell type. Immediately after T cell activation, CD4 T cells can produce both interferon gamma (IFN-gamma) and interleukin 4 (IL-4) before polarization into distinct T helper subsets. Inhibition of IL-4 during mixed allogeneic lymphocyte culture resulted in a defect in the ability of APCs to generate sufficient costimulatory signals for activation of alloreactive T cells. In vivo, a deficiency in IL-4 production inhibited the activation of alloreactive IL-2-, IL-4- and IFN-gamma-producing CD4 T cells in mice challenged with allogeneic skin grafts, resulting in prolonged skin graft survival. Thus, production of IL-4 by CD4T cells helps activate alloreactive T cells by affecting APC function.