Lymphoproliferative disorders involving T helper effector cells with defective LAT signalosomes.

Seminars in Immunopathology
Romain RoncagalliMarie Malissen

Abstract

Linker for activation of T cells (LAT) is a membrane adaptor protein that is expressed in T cells and coordinates the assembly of a multiprotein complex-the LAT signalosome-that links the T cell-specific and the ubiquitous components of the T cell antigen receptor (TCR) signaling pathway. The present review focuses on recent LAT knock-in mice that were found to develop lymphoproliferative disorders involving polyclonal CD4(+) T cells that produced excessive amounts of T helper-type 2 cytokines. These mouse models revealed that LAT constitutes more than just a positive regulator of TCR signaling and plays a negative regulatory role that contributes to terminate antigen-driven T cell responses by exerting a repressive function on components of the TCR signaling cassette that lie upstream of LAT or function independently of LAT. In the absence of such a LAT-operated negative regulatory loop that is intrinsic to conventional CD4(+) T cells and of no lesser importance than the extrinsic regulatory mechanisms mediated by regulatory T cells, physiologic, antigen-specific CD4(+) T cell responses evolve into chronic pro-inflammatory responses that perpetuate themselves in a manner that does not depend on engagement of the TCR and that i...Continue Reading

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