During T-cell development, a pool of precursor immature thymocytes undergoes a complex process of differentiation that results in the generation of two main lineages of mature T cells; CD4 T cells, which act as the orchestrators of the adaptive immune response, and CD8 T cells, which are programmed to elicit cytotoxic functions. The correct undertaking of this process plays a central role in the homeostasis of the immune system and in its ability to successfully control infections while maintaining self-tolerance. I use a genetic approach to understand the molecular events that regulate these differentiation processes.
The mechanisms that regulate CD4/CD8 lineage commitment have been the object of intense study during the last decade. Two main models, stochastic and instructional, were proposed to explain how MHC specificity and co-receptor expression are linked during development. The instructional model proposes that recognition and co-engagement of TCR/CD8 by class I MHC or of TCR/CD4 by class II MHC will instruct the cells to follow a CD8 or a CD4 developmental pathway, respectively. IT has been proposed that the distinct instructional signal would be delivered through the co-receptor. My experiments indentified the tyrosine kinase, Lck, as the critical component in this process. Subsequent experiments in my laboratory showed that the transcription factor, GATA-3, is also a central component of the program that directs development of CD4 T cells in the thymus.
The main focus of my laboratory at the moment is to understand how GATA-3 controls this lineage decision. To that intent, we are trying to a) determine the signal transduction elements that regulate GATA-3 expression during CD4/CD8 lineage commitment, connecting it to the Lck signals at this state; b)analyze the mechanism of action of GATA-3 using structure-function analysis; c) identify GATA-3 targets during CD4 lineage differentiation in the thymus; and d) understand the interactions between GATA-3 and TH-POK, a zinc-finger transcription factor recently identified as a central player in the development of the CD4 lineage.