Role of the LAT adaptor in T-cell development and Th2 differentiation

Abstract

LAT (linker for activation of T cells) is an integral membrane adaptor protein that constitutes in T cells a major substrate of the ZAP-70 protein tyrosine kinase. LAT coordinates the assembly of a multiprotein signaling complex through phosphotyrosine-based motifs present within its intracytoplasmic segment. The resulting "LAT signalosome" links the TCR to the main intracellular signalling pathways that regulate T-cell development and T-cell function. Early studies using transformed T-cell lines suggested that LAT acts primarily as a positive regulator of T-cell receptor (TCR) signalling. The partial or complete inhibition of T-cell development observed in several mouse lines harboring mutant forms of LAT was congruent with that view. More recently, LAT "knock-ins" harboring point mutations in the four COOH-terminal tyrosine residues, were found to develop lymphoproliferative disorders involving polyclonal T cells that produced high amounts of T helper-type 2 (Th2) cytokines. This unexpected finding revealed that LAT also constitutes a negative regulator of TCR signalling and T-cell homeostasis. Although LAT is also expressed in mast cells, natural killer cells, megakaryocytes, platelets, and early B cells, the present review specifically illustrates the role LAT plays in the development and function of mouse T cells. As discussed, the available data underscore that a novel immunopathology proper to defective LAT signalosome is taking shape.