Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor

Michael Mingueneau; Romain Roncagalli; Claude Grégoire; Adrien Kissenpfennig; Arkadiusz Miazek; Cristel Archambaud; Ying Wang; Pierre Perrin; Elodie Bertosio; Amandine Sansoni; Sylvie Richelme; Richard M Locksley; Enrique Aguado; Marie Malissen; Bernard Malissen

doi:10.1016/j.immuni.2009.05.013

Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor

Immunity. 2009 Aug 21;31(2):197-208. doi: 10.1016/j.immuni.2009.05.013. Epub 2009 Aug 13.

Authors

Michael Mingueneau¹, Romain Roncagalli, Claude Grégoire, Adrien Kissenpfennig, Arkadiusz Miazek, Cristel Archambaud, Ying Wang, Pierre Perrin, Elodie Bertosio, Amandine Sansoni, Sylvie Richelme, Richard M Locksley, Enrique Aguado, Marie Malissen, Bernard Malissen

Affiliation

¹ Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, 13288 Marseille Cedex 9, France.

PMID: 19682930
DOI: 10.1016/j.immuni.2009.05.013

Abstract

Despite compromised T cell antigen receptor (TCR) signaling, mice in which tyrosine 136 of the adaptor linker for activation of T cells (LAT) was constitutively mutated (Lat(Y136F) mice) accumulate CD4(+) T cells that trigger autoimmunity and inflammation. Here we show that equipping postthymic CD4(+) T cells with LATY136F molecules or rendering them deficient in LAT molecules triggers a lymphoproliferative disorder dependent on prior TCR engagement. Therefore, such disorders required neither faulty thymic T cell maturation nor LATY136F molecules. Unexpectedly, in CD4(+) T cells recently deprived of LAT, the proximal triggering module of the TCR induced a spectrum of protein tyrosine phosphorylation that largely overlapped the one observed in the presence of LAT. The fact that such LAT-independent signals result in lymphoproliferative disorders with excessive cytokine production demonstrates that LAT constitutes a key negative regulator of the triggering module and of the LAT-independent branches of the TCR signaling cassette.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / immunology*
Adoptive Transfer
Animals
CD28 Antigens / immunology*
CD28 Antigens / metabolism
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Cytokines / immunology
Cytokines / metabolism
Histocompatibility Antigens Class II / immunology*
Histocompatibility Antigens Class II / metabolism
Lymphoproliferative Disorders / genetics
Lymphoproliferative Disorders / immunology*
Membrane Proteins / genetics
Membrane Proteins / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Mutation
Phosphoproteins / genetics
Phosphoproteins / immunology*
Phosphorylation / immunology
Receptors, Antigen, T-Cell / immunology*
Receptors, Antigen, T-Cell / metabolism
Signal Transduction / immunology

Substances

Adaptor Proteins, Signal Transducing
CD28 Antigens
Cytokines
Histocompatibility Antigens Class II
Lat protein, mouse
Membrane Proteins
Phosphoproteins
Receptors, Antigen, T-Cell