RESUMO
Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80(+) lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance.
Assuntos
Tolerância Imunológica , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Hipersensibilidade Respiratória/imunologia , Linfócitos T/imunologia , Administração Intranasal , Transferência Adotiva , Animais , Anticorpos Bloqueadores/administração & dosagem , Antígenos/imunologia , Antígenos de Diferenciação/metabolismo , Células Cultivadas , Linfonodos/patologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fagocitose/imunologiaRESUMO
The TIM gene family was discovered seven years ago by positional cloning in a mouse model of asthma and allergy. Three of the family members (TIM-1, TIM-3, and TIM-4) are conserved between mouse and man, and have been shown to critically regulate adaptive immunity. In addition, TIM-1 has been shown to play a major role as a human susceptibility gene for asthma, allergy and autoimmunity. Recently, TIM-4 has been identified as a ligand of phosphatidylserine and to control the uptake of apoptotic cells. These studies together suggest that the TIM gene family evolved to regulate immune responses by managing survival and cell death of hematopoetic cells.
Assuntos
Hipersensibilidade/etiologia , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana/fisiologia , Receptores Virais/fisiologia , Animais , Doenças Autoimunes/etiologia , Cristalização , Receptor Celular 1 do Vírus da Hepatite A , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Hipersensibilidade/genética , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Camundongos , Receptores Virais/química , Receptores Virais/genética , Linfócitos T/imunologiaRESUMO
To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.
