RESUMO
T cell sensitivity to antigen is intrinsically regulated during maturation to ensure proper development of immunity and tolerance, but how this is accomplished remains elusive. Here we show that increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, while inhibiting miR-181a expression in the immature T cells reduces sensitivity and impairs both positive and negative selection. Moreover, quantitative regulation of T cell sensitivity by miR-181a enables mature T cells to recognize antagonists-the inhibitory peptide antigens-as agonists. These effects are in part achieved by the downregulation of multiple phosphatases, which leads to elevated steady-state levels of phosphorylated intermediates and a reduction of the T cell receptor signaling threshold. Importantly, higher miR-181a expression correlates with greater T cell sensitivity in immature T cells, suggesting that miR-181a acts as an intrinsic antigen sensitivity "rheostat" during T cell development.
Assuntos
MicroRNAs/fisiologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular , Linhagem Celular Tumoral , Citocromos c/química , Citocromos c/imunologia , Regulação para Baixo , Regulação da Expressão Gênica , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Mariposas , Células NIH 3T3 , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Técnicas de Cultura de Órgãos , Peptídeos/imunologia , Monoéster Fosfórico Hidrolases/genética , Receptores de Antígenos de Linfócitos T/agonistas , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/metabolismo , Timo/citologia , Timo/imunologia , Timo/metabolismoRESUMO
During infection of their hosts, Gram-positive bacteria express surface proteins that serve multiple biological functions. Surface proteins harbouring a C-terminal sorting signal with an LPXTG motif are covalently linked to the cell wall peptidoglycan by a transamidase named sortase. Two genes encoding putative sortases, termed srtA and srtB, were identified in the genome of the intracellular pathogenic bacterium Listeria monocytogenes. Inactivation of srtA abolishes anchoring of the invasion protein InlA to the bacterial surface. It also prevents the proper sorting of several other peptidoglycan-associated LPXTG proteins. Three were identified by a mass spectrometry approach. The DeltasrtA mutant strain is defective in entering epithelial cells, similar to a DeltainlA mutant. In contrast to a DeltainlA mutant, the DeltasrtA mutant is impaired for colonization of the liver and spleen after oral inoculation in mice. Thus, L. monocytogenes srtA is required for the cell wall anchoring of InlA and, presumably, for the anchoring of other LPXTG-containing proteins that are involved in listerial infections.