T cells as sources and targets of TNF: implications for immunity and autoimmunity.

TNF is a pleiotropic cytokine produced by many cell types upon different stimuli and in various physiological and pathological conditions. In this review, we focus on the role of TNF in T cell responses as demonstrated by in vitro and in vivo observations in mice and humans. TNF has an impact on all aspects of T cell biology such as development in the thymus, peripheral homeostasis, primary antigenic responses, apoptosis, effector functions, memory cell formation and tolerance induction and maintenance. In most cases, TNF has an immunostimulatory role in T cell responses; however, under certain conditions, TNF can exert immunomodulatory effects on T cells. We also review how T cell-derived TNF is an important component of T cell immunity as exemplified by many studies involving intracellular pathogens and tumors. Finally, we summarize how TNF T cells interplay contributes to pathology in autoimmune disorders and what is known about the effect of widely used TNF blockers on T cell differentiation/function.