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

M. Mingueneau, R. Roncagalli, C. Grégoire, Adrien Kissenpfennig, A. Miazek, C. Archambaud, Y. Wang, P. Perrin, E. Bertosio, A. Sansoni, S. Richelme, R.M. Locksley, E. Aguado

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79 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)197-208
Number of pages12
JournalImmunity
Volume31(2)
Issue number2
DOIs
Publication statusPublished - 21 Aug 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

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