Abstract
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.
Highlights
T effector cells, T regulatory cells (Tregs) play a critical role in counteracting an over-activated immune action that occurs in response to exogenous pathogens and self- or allo-antigens
ConAinduced liver injury in mice is a well-characterized model of T cell-mediated liver disease depends on the activation of T lymphocytes by macrophages in the presence of Concanavalin A (ConA) and has been extensively used to mimic many aspects of human T cell-mediated liver disease.[12,21,22]
In addition to the expected pathological necrosis of hepatocytes described after ConA treatment, we found that peripheral double-negative T cells (DNT) were unexpectedly induced, increasing up to threefold in a dose- and timedependent manner compared with untreated controls
Summary
T effector cells, T regulatory cells (Tregs) play a critical role in counteracting an over-activated immune action that occurs in response to exogenous pathogens and self- or allo-antigens. Concanavalin A (ConA)-induced necro-inflammatory damage of the liver is a well-accepted immunological model of liver injury, which occurs primarily through over-activation of CD4+ T cells, Kupffer cells and NKT cells.[12,13,14] It is well known that CD4+ T cells can differentiate into Tregs as well as Th1, Th2, Th9, Th22, Tfh and Th17 T cells, depending on the specific cytokine milieu These various types of T cells develop to exert a variety of different immune functions and to maintain the balance between immune invading and protecting components.[15,16,17,18,19]. We revealed a novel differentiation pathway, which converts over-activated CD4+ T cells into a subset of regulatory T cells (DNT), which would serve as an immune defense against ConA-induced liver injury in vivo, for maintaining immune system homeostasis
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