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

Abstract

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.

Fig. 1

Th1 cells stimulated with TCR engagement in the absence of costimulation via CD28 (Th1 Cell-Anergic Conditions) upregulate expression of many genes, a subset of which encode inhibitors of the full T cell activation program (indicated by “X”) resulting in decreased proliferation and IL-2 secretion termed anergy. Upon full activation including CD28 costimulation, activation of mTOR leads to the net expression/activation of activating proteins (indicated by “O”) outweighing inhibitory genes, permitting normal cytokine expression and proliferation (Th1 Cell-Activating Conditions). In the context of full activation of a naïve CD4 T cell (Naïve T cell), integration of multiple costimulatory signals including CD28 costimulation, cytokine expression, and sensing of available nutrients collectively activate mTOR. The result is expression of many proteins that overlap those involved in inhibition and activation of differentiated Th1 cells (indicated by “X” and “O”); but in this cellular context, the gene products participate in commitment of the cell to a differentiated Th effector fate