RESUMO
OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer (Lti) cells, a subset of group 3 innate lymphoid cells (ILC3s). OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown. Here, we showed intestinal ILC3s marked as an OX40Lhigh population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1-/- mice. All ILC3 subsets expressed OX40L, and NCR-ILC3s were the most abundant source of OX40L. The expression of OX40L in ILC3s could be upregulated during inflammation. In addition to tumor necrosis factor (TNF)-like cytokine 1A (TL1A), which has been known as a trigger for OX40L, we found that Poly (I:C) representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner. Furthermore, we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s. Intestinal regulatory T cells (Tregs), most of which expressed OX40, had defective expansion in chimeric mice, in which ILC3s were specifically deficient for OX40L expression. Consistently, co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine, which suggests the close interaction between ILC3s and Tregs. Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40-OX40L signaling, which is crucial for the homeostasis of intestinal Tregs.
Assuntos
Homeostase/genética , Homeostase/imunologia , Hospedeiro Imunocomprometido/genética , Mucosa Intestinal/imunologia , Ligante OX40/deficiência , Transdução de Sinais/genética , Linfócitos T Reguladores/imunologia , Animais , Comunicação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imunidade Inata , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligante OX40/genética , Receptores OX40/metabolismo , Transdução de Sinais/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
CD4(+) T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4(+) T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4(-)CD8(-)NK1.1(-) double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4(+) rather than CD8(+) T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4(+) T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases.
