RESUMO
Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT. On TCR stimulation of T cells from these mice, proximal signaling and cytokine production was elevated in 2KR versus wild-type (WT) LAT mice. Enhanced cytolytic activity as well as T-helper responses were observed on LAT expression, which were further elevated by 2KR LAT expression. Despite greater T-effector function, WT or 2KR LAT expression did not have any effect on clearance of certain pathogens or tumors. Our data support the model that lack of tumor clearance is due to increased differentiation and acquisition of effector phenotype that is associated with suboptimal immunity in an immunotherapy model. Thus, our data further reinforce the role of LAT ubiquitination in TCR signaling and uncovers a novel role for LAT in driving T-cell differentiation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ativação Linfocitária , Linfócitos/imunologia , Proteínas de Membrana/genética , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Substituição de Aminoácidos , Animais , Diferenciação Celular/genética , Ativação Linfocitária/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Transgênicos , Fosfoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , UbiquitinaçãoRESUMO
Regulatory T cells (T(reg)) control an array of immune responses both in the context of various polarized settings as well as in distinct microenvironments. This implies that maintenance of peripheral homeostasis relies on the capacity of T(reg) to appropriately adapt to these defined settings while sustaining a regulatory program in the face of inflammation. Adaptation of T(reg) is particularly critical in tissues constantly exposed to microbes, such as the gut or the skin, or in the context of exposure to pathogenic microbes. Recent evidence supports the idea that the capacity of T(reg) to control defined polarized settings can be associated with the acquisition of specific transcription factors previously associated with effector T-cell lineages. In this review we will discuss how such adaptation of T(reg) can have a major role in the control of host-microbe interaction.
