RESUMEN
T cell immunoglobulin and mucin domain 3 (Tim3) is a negative regulatory molecule that inhibits effector T(H)1-type responses. Such inhibitory signals prevent unintended tissue inflammation, but can be detrimental if they lead to premature T cell exhaustion. Although the role of Tim3 in autoimmunity has been extensively studied, whether Tim3 regulates antimicrobial immunity has not been explored. Here, we show that Tim3 expressed on T(H)1 cells interacts with its ligand, galectin-9 (Gal9), which is expressed by Mycobacterium tuberculosis-infected macrophages to restrict intracellular bacterial growth. Tim3-Gal9 interaction leads to macrophage activation and stimulates bactericidal activity by inducing caspase-1-dependent IL-1ß secretion. We propose that the T(H)1 cell surface molecule Tim3 has evolved to inhibit growth of intracellular pathogens via its ligand Gal9, which in turn inhibits expansion of effector T(H)1 cells to prevent further tissue inflammation.
Asunto(s)
Galectinas/inmunología , Macrófagos Peritoneales/inmunología , Mycobacterium tuberculosis/inmunología , Receptores Virales/inmunología , Células TH1/inmunología , Tuberculosis/inmunología , Animales , Caspasa 1/genética , Caspasa 1/inmunología , Caspasa 1/metabolismo , Galectinas/genética , Galectinas/metabolismo , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Receptor 2 Celular del Virus de la Hepatitis A , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/microbiología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/microbiología , Ratones , Ratones Noqueados , Mycobacterium tuberculosis/metabolismo , Receptores Virales/genética , Receptores Virales/metabolismo , Células TH1/metabolismo , Células TH1/microbiología , Tuberculosis/genética , Tuberculosis/metabolismoRESUMEN
Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1.