Genetic and biochemical regulation of CD4 T cell effector differentiation: insights from examination of T cell clonal anergy

The two-signal model of T cell activation states that antigen recognition by TCR provides a tolerogenic signal (termed Signal 1) unless the T cell receives simultaneous costimulation (Signal 2) that permits antigen recognition to prime activation. Our efforts to characterize genetic and biochemical factors resulting from Signal 1 alone have identified signaling molecules, transcription factors, and an epigenetic regulator that each contribute to the anergic phenotype observed. However, our most striking finding is that the same factors identified using anergy to model T cell activation versus tolerance also participate in determining the outcome of the effector phenotype of fully activated T cells. We summarize our own findings and other recent advances in the genetic and biochemical understanding of T cell activation, tolerance, and plasticity in this review.