Th2 lymphoproliferative disorders resulting from defective LAT signalosomes.
LAT (linker for activation of T cells) is an integral membrane adaptor protein that constitutes in T cells a major substrate of the ZAP-70 protein tyrosine kinase. LAT coordinates the assembly of a multiprotein signalling complex through phosphotyrosine-based motifs present within its intracytoplasmic segment. The resulting 'LAT signalosome' links the TCR to the main intracellular signalling pathways that regulate T cell development and T cell function. Early studies using transformed T cell lines suggested that LAT acts primarily as a positive regulator of T cell receptor (TCR) signalling. The partial or complete inhibition of T cell development observed in several mouse lines harbouring mutant forms of LAT was congruent with that view. More recently, LAT 'knock-ins' harbouring point mutations in the four COOH-terminal tyrosine residues, were found to develop lymphoproliferative disorders involving polyclonal T cells that produced high amounts of T helper-type 2 (Th2) cytokines. This unexpected finding revealed that LAT also constitutes a negative regulator of TCR signalling and T cell homeostasis. As discussed, the available data underscore that a novel immunopathology proper to defective LAT signalosome is likely taking shape.
Malissen
Bernard
B
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, 13288 Marseille, France.
Wang
Ying
Y
Mingueneau
Michael
M
Malissen
Marie
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D000818:Animals; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008565:Membrane Proteins