The development of T lymphocytes occurs in the thymus according to a prescribed differentiation program that is characterized by ordered changes in expression of particular cell surface proteins (Figure 1). This differentiation program occurs in two phases. The first phase (DN1-DN3) involves commitment of immature precursors to the T cell lineage. The second phase of development (DN3-SP) involves the production and evaluation of the T cell antigen receptor (TCR) complex through which T lymphocytes recognize their targets. The TCR is a modular receptor consisting of a set of invariant signaling subunits (CD3γδε and ζ) and a heterodimer of diverse ligand-binding subunits (either αβ or γδ) that enables each T cell to bind a different ligand. The ligand-binding subunits are constructed by "V(D)J recombination," which entails the joining of widely dispersed gene segments into a single coding unit. The TCR complexes play a crucial role in regulating all subsequent steps of thymocyte development. Two processes of particular interest are β-selection and αβ/γδ lineage commitment. β-selection refers to the selective survival of thymocytes that have successfully recombined the TCRβ locus. Successful β-rearrangement results in expression of the TCRβ protein and the activation of a TCR isoform called the pre-TCR complex. Pre-TCR activation results not only in survival, but also proliferative expansion, maturation of DN3 thymocytes to the DP stage, and termination of TCRβ rearrangement (i.e., allelic exclusion). αβ/γδ lineage commitment is the process whereby immature thymocytes with the capacity to express either γδ or αβ TCR complexes chose which lineage they will ultimately become. αβ and γδ T cells play vital, somewhat distinct roles in immune responses and are thought to arise from a common precursor in the thymus; but the signals directing lineage choice remain unclear.
Figure 1
Currently, the research in our laboratory is focused on understanding:
