RESUMO
Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)alpha (iTCRalpha) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and gammadelta T cells.
Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade nas Mucosas/imunologia , Células T Matadoras Naturais/fisiologia , Subpopulações de Linfócitos T/fisiologia , Timo/imunologia , Animais , Linfócitos B/fisiologia , Criança , Sangue Fetal/imunologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Proteína com Dedos de Zinco da Leucemia Promielocítica , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T , Timo/citologiaRESUMO
Host resistance to the intracellular protozoan Toxoplasma gondii is highly dependent on early IL-12 production by APC. We demonstrate here that both host resistance and T. gondii-induced IL-12 production are dramatically reduced in mice lacking the adaptor molecule MyD88, an important signaling element used by Toll-like receptor (TLR) family members. Infection of MyD88-deficient mice with T. gondii resulted in uncontrolled parasite replication and greatly reduced plasma IL-12 levels. Defective IL-12 responses to T. gondii Ags (soluble tachyzoite Ag (STAg)) were observed in MyD88(-/-) peritoneal macrophages, neutrophils, and splenic dendritic cells (DC). In contrast, DC from TLR2- or TLR4-deficient animals developed normal IL-12 responses to STAg. In vivo treatment with pertussis toxin abolished the residual IL-12 response displayed by STAg-stimulated DC from MyD88(-/-) mice. Taken together, these data suggest that the induction of IL-12 by T. gondii depends on a unique mechanism involving both MyD88 and G protein-coupled signaling pathways.
Assuntos
Antígenos de Diferenciação/fisiologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Proteínas de Drosophila , Interleucina-12/biossíntese , Receptores Imunológicos/fisiologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Toxoplasmose Animal/parasitologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos de Diferenciação/genética , Células Dendríticas/parasitologia , Feminino , Imunidade Inata/genética , Interferon gama/biossíntese , Interferon gama/deficiência , Interleucina-12/deficiência , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Receptores CCR5/fisiologia , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/fisiologia , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Transdução de Sinais/imunologia , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-Like , Toxoplasmose Animal/genética , Toxoplasmose Animal/mortalidadeRESUMO
The evolutionary conservation of T lymphocyte subsets bearing T-cell receptors (TCRs) using invariant alpha-chains is indicative of unique functions. CD1d-restricted natural killer T (NK-T) cells that express an invariant Valpha14 TCRalpha chain have been implicated in microbial and tumour responses, as well as in auto-immunity. Here we show that T cells that express the canonical hValpha7.2-Jalpha33 or mValpha19-Jalpha33 TCR rearrangement are preferentially located in the gut lamina propria of humans and mice, respectively, and are therefore genuine mucosal-associated invariant T (MAIT) cells. Selection and/or expansion of this population requires B lymphocytes, as MAIT cells are absent in B-cell-deficient patients and mice. In addition, we show that MAIT cells are selected and/or restricted by MR1, a monomorphic major histocompatibility complex class I-related molecule that is markedly conserved in diverse mammalian species. MAIT cells are not present in germ-free mice, indicating that commensal flora is required for their expansion in the gut lamina propria. This indicates that MAIT cells are probably involved in the host response at the site of pathogen entry, and may regulate intestinal B-cell activity.