Increased Protein Stability and Interleukin-2 Production of a LATG131D Variant With Possible Implications for T Cell Anergy.

Arbulo-Echevarria, Mikel MVico-Barranco, InmaculadaNarbona-Sanchez, IsaacGarcia-Cozar, FranciscoMiazek, ArkadiuszAguado, Enrique2023-02-092023-02-092020-08-13Arbulo-Echevarria MM, Vico-Barranco I, Narbona-Sánchez I, García-Cózar F, Miazek A, Aguado E. Increased Protein Stability and Interleukin-2 Production of a LATG131D Variant With Possible Implications for T Cell Anergy. Front Cell Dev Biol. 2020 Sep 11;8:5615032296-634Xhttp://hdl.handle.net/10668/16400The adaptor LAT plays a crucial role in the transduction of signals coming from the TCR/CD3 complex. Phosphorylation of some of its tyrosines generates recruitment sites for other cytosolic signaling molecules. Tyrosine 132 in human LAT is essential for PLC-γ activation and calcium influx generation. It has been recently reported that a conserved glycine residue preceding tyrosine 132 decreases its phosphorylation kinetics, which constitutes a mechanism for ligand discrimination. Here we confirm that a LAT mutant in which glycine 131 has been substituted by an aspartate (LATG131D) increases phosphorylation of Tyr132, PLC-γ activation and calcium influx generation. Interestingly, the LATG131D mutant has a slower protein turnover while being equally sensitive to Fas-mediated protein cleavage by caspases. Moreover, J.CaM2 cells expressing LATG131D secrete greater amounts of interleukin-2 (IL-2) in response to CD3/CD28 engagement. However, despite this increased IL-2 secretion, J.CaM2 cells expressing the LATG131D mutant are more sensitive to inhibition of IL-2 production by pre-treatment with anti-CD3, which points to a possible role of this residue in the generation of anergy. Our results suggest that the increased kinetics of LAT Tyr132 phosphorylation could contribute to the establishment of T cell anergy, and thus constitutes an earliest known intracellular event responsible for the induction of peripheral tolerance.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/IL-2 (interleukin-2)LATTCRAnergyPhosphorylationReceptor-CD3 complex, antigen, T-cellPhosphorylationLigandsPeripheral toleranceT-lymphocytesTyrosineCaspasesGlycineIncreased Protein Stability and Interleukin-2 Production of a LATG131D Variant With Possible Implications for T Cell Anergy.Research article33042995open accessCaspasasComplejo receptor-CD3 del antígeno de linfocito TFosforilaciónGlicinaLigandosLinfocitos TTirosinaTolerancia periférica10.3389/fcell.2020.561503PMC7517355https://www.frontiersin.org/articles/10.3389/fcell.2020.561503/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517355/pdf