In response to antigen recognition, resting T lymphocytes undergo a complex series of events known as T-cell activation that initiates signal transduction pathways leading to T cell proliferation, activation induced cell death, cytokine production, or cytolysis. However, T cell antigen receptor (TCR/CD3) signaling is not sufficient to control activation of resting T cells: co-stimulatory signals through for instance CD4/8, CD28/CTLA4 need to be provided. Although much has been learned about T-cell activation, an orderly array of the molecular events involved in the whole process remains to be established. Immediately following T-cell antigen recognition the CD3 proteins recruit non-receptor-protein-tyrosine kinases to phosphorylate the CD3 Immunerceptor Tyrosine Activation Motifs (ITAMS). The four principal pathways that potentially ensue upon tyrosinephosphorylation of the CD3 ITAMs are: the MAP-kinase pathways, the Calcineurin pathway, a PKC and a PI3'-kinase pathway. We will concentrate our efforts on the biochemical reactions which couple CD3-zeta and CD3-epsilon to the MAP kinase pathways. Regulation of the early biochemical steps from CD3-epsilon and CD3-zeta towards Ras and the Rho family GTP binding proteins appear to be critical in the precise control of T cell activation. Our general hypothesis is that most of the biochemical events that regulate responsiveness to antigens are proximal to the CD3 proteins. Specifically we propose to: -Analyze the initial biochemical steps leading from CD3-zeta or CD3- epsilon to Ras in the activation of the MAP kinase Raf-1. -Test the hypothesis that the 14.3.3/CD3-zeta complex provides a scaffold upon which some of the pathways between CD3-zeta and Raf are initiated. -Test the hypothesis that a Rho family GTP binding protein complexes with CD3-zeta to activate the MAP-kinases JNK and p38. -Further study the in vitro TCR signal transduction in peripheral CD4 plus and CD8 plus T lymphocytes from CD3-zeta/eta null mice.
Showing the most recent 10 out of 58 publications
