Mutation of the glycine residue preceding the sixth tyrosine of the LAT adaptor severely alters T cell development and activation.

The LAT transmembrane adaptor is essential to transduce intracellular signals triggered by the TCR. Phosphorylation of its four C-terminal tyrosine residues (136, 175, 195, and 235 in mouse LAT) recruits several proteins resulting in the assembly of the LAT signalosome. Among those tyrosine residues, the one found at position 136 of mouse LAT plays a critical role for T cell development and activation. The kinetics of phosphorylation of this residue is delayed as compared to the three other C-terminal tyrosines due to a conserved glycine residue found at position 135. Mutation of this glycine into an aspartate residue (denoted LATG135D) increased TCR signaling and altered antigen recognition in human Jurkat T cells and ex vivo mouse T cells. Here, using a strain of LATG135D knockin mice, we showed that the LATG135D mutation modifies thymic development, causing an increase in the percentage of CD4+CD8+ double-positive cells, and a reduction in the percentage of CD4+ and CD8+ single-positive cells. Interestingly, the LATG135D mutation alters thymic development even in a heterozygous state. In the periphery, the LATG135D mutation reduces the percentage of CD8+ T cells and results in a small increment of γδ T cells. Remarkably, the LATG135D mutation dramatically increases the percentage of central memory CD8+ T cells. Finally, analysis of the proliferation and activation of T lymphocytes shows increased responses of T cells from mutant mice. Altogether, our results reinforce the view that the residue preceding Tyr136 of LAT constitutes a crucial checkpoint in T cell development and activation.

Activación de la célula T, alteraciones en el lupus eritematoso sistémico, una revisión narrativa / T-cell activation, alterations in systemic lupus erythematosus: A narrative review

Resumen La activación de los linfocitos T se inicia a través de la presentación de antígenos endógenos o exógenos por células presentadoras de antígenos a través del complejo mayor de histocompatibilidad, el cual se une a un receptor especializado presente en los linfocitos T. Este reconocimiento desencadena una cascada de señalización intracelular que conlleva a un aumento en la expresión de integrinas, modificaciones del citoesqueleto y producción de factores de transcripción involucrados en la liberación de citocinas y mediadores inflamatorios. Uno de los inductores más importantes en la activación celular es el complejo enzimático con acción tirosina cinasa. Las cinasas que pertenecen a la familia SRC (SFK), FYN y LCK están involucradas en un gran número de procesos importantes en la activación, modulación de la respuesta linfocitaria y el desarrollo de enfermedades autoinmunes. La regulación de la señalización de las cinasas, así como de proteínas adaptadoras involucradas en la activación del linfocito T, son fundamentales para mantener el umbral de activación y modulación de la respuesta del linfocito. La fosforilación de sitios de regulación positiva de estas proteínas es importante para permitir una configuración activa de la proteína y de esta forma su máxima capacidad como cinasa. La fosforilación de los sitios de regulación negativa conlleva a una configuración cerrada de la proteína de tal forma que reduce su función de cinasa e inhibe su función. Las alteraciones en la señalización por modificación de algunas proteínas citoplasmáticas se asocian en algunos casos al desarrollo de enfermedades autoinmunes, como el lupus eritematoso sistémico. En condiciones fisiológicas, el complejo receptor de linfocitos T se reagrupa con complejos proteicos que interactúan armónicamente para generar una sen al interna. Los eventos de señalización alterados son en parte los responsables de una expresión anómala de citocinas, entre ellas la interleucina-6 (IL-6), IL-10, IL-2, IFN y CD40 ligando; estas modificaciones alteran la capacidad de los linfocitos T para sobre estimular a los linfocitos B, traduciéndose en un aumento en la producción de autoanticuerpos y en el desencadenamiento de la enfermedad autoinmune.

Abstract The activation of T cells is initiated by the presentation of exogenous or endogenous antigens, by antigen presenting cells through the major histocompatibility complex, which binds to a special receptor on T cells. This acknowledgement triggers a cascade of intracellular signalling that leads to an increase in integrin expression, cytoskeletal modifications, and transcription factors production involved in the liberation of cytokines and inflammatory mediators. One of the most important inducers in cell activation is the enzymatic complex with tyrosine kinase action. The kinases which belong to the SRC (SFK) LCK and FYN family have been involved in a large number of important processes in the activation and modulation of the T cells response, as well as in the development of autoimmune diseases. Regulating the kinases signalling, as well as the adapter proteins involved in T cell activation, is essential for maintaining an activation threshold, as well as the modulation of cell response. The phosphorylation of the positive regulation sites of these proteins is important to allow an active configuration of the protein and thereby its maximum capacity as kinase. The phosphorylation of negative regulation sites leads to a closed configuration of the protein that reduces its kinase function, and thereby inhibits its own function. The alteration in signalling by the modification of certain cytoplasmic proteins in some cases is associated with the development of autoimmune diseases, such as systemic lupus erythematosus. Under physiological conditions the T cell receptor complex regroups with protein complexes that interact harmonically to generate an internal signal. The altered signalling events are partly responsible for an anomalous expression of cytokines, including the interleukin-6 (IL-6), IL-10, IL-2, IFN, and CD40 linking, these modifications affects the cells ability to over-stimulate T and B cells, resulting in an increased production of autoantibodies and the triggering of the autoimmune disease.

Effect of Bromocriptine on the Activation of T Lymphocyte Stimulated by Phytohemagglutinin / 实用儿科临床杂志

Objective To study the effect of bromocriptine(BRC) on the activation of T lymphocyte stimulated by phytohemagglutinin(PHA).Methods After CD4+ T cell line Jurkat E6-1 cells were stimulated by PHA,prolactin(PRL) and BRC,respectively,the expression of linker for activation of T cells(LAT) and zeta-chain T cell receptor associated protein kinase 70 000(ZAP-70) mRNA of T lymphocytes were checked by RT-PCR.The expression of PRL mRNA of T lymphocytes was detected by Real time PCR.The expression of CD25(cluster of differentiation) as a marker of early activation on the surface of T lymphocytes was detected by flow cytometry,and the activation of nuclear factor-?B(NF-?B) was detected by luciferase reporter system.Results 1.BRC inhibited the expression of ZAP-70 as the common signal molecules both in the T lymphocyte activation pathway and PRL-prolactin-prolactin receptor(PRLR) signal transduction pathway,and decreased the expression of PRL mRNA produced by activation T lymphocytes.2.BRC enhanced the expression of LAT mRNA as another important signal molecular on the T lymphocytes and CD25 on the surface of the T lymphocytes.3.The activation of NF-?B of T lymphocytes was decreased.Conclusions BRC might inhibit the activation of T lymphocytes by inhibiting the expression of ZAP-70,the common signal molecules between T lymphocytes activation and PRL-PRL pathway,and PRL mRNA,the like-T lymphocyte growth factor.