LAT signaling pathology: an "autoimmune" condition without T cell self-reactivity.
Partial loss-of-function mutations in several molecules involved in T-cell receptor (TCR) signaling result in inflammation and autoimmunity. How can mutations that reduce TCR signaling output, paradoxically lead to immune pathology? This review summarizes experiments demonstrating that mutations in the linker for activation of T cells (LAT) predispose toward aberrant T cell responses to antigen in the presence of normal thymic selection. In the absence of LAT, antigen-specific T cells give rise to self-perpetuating pro-inflammatory responses and induce the production of autoantibodies independently of TCR engagement. Therefore, some pathological conditions called "autoimmune" might not result from the presence of self-reactive T cells, but from defective mechanisms that normally keep T cell activation in check.
Roncagalli
Romain
R
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, 13288 Marseille Cedex 9, France.
Mingueneau
Michael
M
Grégoire
Claude
C
Malissen
Marie
M
Malissen
Bernard
B
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015551:Autoimmunity; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell