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 induce the production of massive amounts of antibodies and autoantibodies in a major histocompatibility complex-II-independent, “quasi-mitogenic” mode. As discussed, these data underscore that a novel immunopathology proper to defective LAT signalosomes is likely taking shape, and we propose to call it “LAT signaling pathology.”
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Acknowledgements
We thank H. Acha-Orbea for discussion. This study is supported by CNRS, INSERM, European Communities (MASTERSWITCH and SYBILLA Integrating Projects), ANR (Plate-forme Technologique du Vivant IBISA), ARC, FRM, and by doctoral fellowships from Ecole Normale Supérieure and ARC (MiM) and postdoctoral fellowships from FNRS (CL) and the European Communities SYBILLA Integrating Project (RR).
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Roncagalli, R., Mingueneau, M., Grégoire, C. et al. Lymphoproliferative disorders involving T helper effector cells with defective LAT signalosomes. Semin Immunopathol 32, 117–125 (2010). https://doi.org/10.1007/s00281-009-0195-y
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DOI: https://doi.org/10.1007/s00281-009-0195-y