Lymphoproliferative disorders involving T helper effector cells with defective LAT signalosomes.
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."
Roncagalli
Romain
R
Centre d'Immunologie de Marseille-Luminy, Case 906, Université de la Méditerranée, 13288, Marseille Cedex 9, France.
Mingueneau
Michael
M
Grégoire
Claude
C
Langlet
Christelle
C
Malissen
Bernard
B
Malissen
Marie
M
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D055879:Gene Knock-In Techniques; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D046912:Multiprotein Complexes / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C491734:Lat protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell