RESUMO
Multiple sclerosis (MS) is a T cell-driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4+ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism. In this study, we characterized MAIT cells from the peripheral blood of MS patients in comparison with healthy individuals with respect to their type-17 differentiation. We found a specific increase of IL-17+ MAIT cells as well as an increased expression of retinoic acid-related orphan receptor (ROR)γt and CCR6 in MAIT cells from MS patients, whereas the expression of T cell activation markers HLA-DR and CD38 was not different. IL-17 production by MAIT cells furthermore correlated with the surface expression level of the IL-7 receptor α-chain (CD127), which was significantly increased on MAIT cells from MS patients in comparison with healthy individuals. In summary, our findings indicate an augmented type-17 differentiation of MAIT cells in MS patients associated with their IL-7 receptor surface expression, implicating a proinflammatory role of these unconventional T cells in MS immunopathology.
Assuntos
Sistema Nervoso Central/patologia , Interleucina-17/biossíntese , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Células T Invariantes Associadas à Mucosa/imunologia , Esclerose Múltipla/patologia , ADP-Ribosil Ciclase 1/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Sistema Nervoso Central/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Esclerose Múltipla/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Receptores de Antígenos de Linfócitos T/imunologia , Receptores CCR6/biossíntese , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/imunologia , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Interleukin-7 (IL-7) has been studied for its possible immunorestorative capacities following stem cell transplantation and has been shown to enhance post-transplant immune recovery predominantly by peripheral T-cell expansion. A major concern of IL-7 is its possible aggravating effect on graft-versus-host and host-versus-graft reactivity. DESIGN AND METHODS: To study the effect of IL-7 on host-versus-graft reactivity, we applied IL-7 in an experimental transplantation model using RAG-1-/- mice supplied with B6 CD45.1 congenic T cells as recipients of T-cell depleted allogeneic bone marrow grafts. RESULTS: Rejection of minor antigen-mismatched bone marrow was significantly reduced in IL-7 treated recipients compared with PBS treated control mice. Rejection was observed in 2 out of 18 IL-7 treated mice compared with 9 out of 17 PBS treated mice (11% vs. 53%; p=0.012). IL-7 administration resulted in enhanced recovery of peripheral blood CD4+CD25+ regulatory T cells (Treg) with a concomitant increase in peripheral blood Foxp3 mRNA expression. IL-7Ra (CD127) was expressed by the vast majority of CD4+Foxp3+ T cells. The incidence of graft rejection following fully MHC mismatched bone marrow transplantation was not reduced nor enhanced by IL-7 administration. INTERPRETATION AND CONCLUSIONS: Post-transplant IL-7 administration protects against minor antigen-mismatched bone marrow rejection, which may be due to enhanced Treg recovery.