TY - JOUR
T1 - Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor.
AU - Mingueneau, M.
AU - Roncagalli, R.
AU - Grégoire, C.
AU - Kissenpfennig, Adrien
AU - Miazek, A.
AU - Archambaud, C.
AU - Wang, Y.
AU - Perrin, P.
AU - Bertosio, E.
AU - Sansoni, A.
AU - Richelme, S.
AU - Locksley, R.M.
AU - Aguado, E.
PY - 2009/8/21
Y1 - 2009/8/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=68649087416&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2009.05.013
DO - 10.1016/j.immuni.2009.05.013
M3 - Article
C2 - 19699166
VL - 31(2)
SP - 197
EP - 208
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 2
ER -