Autoantigen and IL-2 activated CD4+CD25+T regulatory cells are induced to express CD8 and are autoantigen specific in inhibiting experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin basic protein (MBP) is a self-limiting disease model of multiple sclerosis. CD4⁺CD25⁺Foxp3⁺T cells play a role in limiting autoimmune disease but treatment with antigen naïve CD4⁺CD25⁺ cells does not reduce EAE.

This study examined if in vitro activation by MBP and rIL-2 induced CD4⁺CD25⁺Foxp3⁺ cells that could inhibit EAE. Culture of CD4⁺CD8^-CD25⁺cells from naïve rats with MBP and rIL-2 induced activated Treg that reduced the severity of clinical EAE and infiltration of CD8⁺T cells and macrophage into brain stem. CD4⁺CD25⁺T cells activated by an irrelevant autoantigen and rIL-2 did not suppress EAE. Resting CD4⁺CD25⁺T cells activated by autoantigen and rIL-2 have mRNA for Infgr, Il12rb2, Il5 but not Tbet, Gata3, Ilr5ra or Ifng. These changes in mRNA expression are the markers of Ts1 cells.

A proportion of CD4⁺CD8^-CD25⁺ cells activated by MBP/rIL-2 were induced to express CD8α, CD8β and CD62L. Depletion of CD4⁺CD8α⁺CD25⁺ cells removed the capacity of MBP and rIL-2 activated CD4⁺CD25⁺T cells to suppress EAE.

This study demonstrated that in vitro activation of CD4⁺CD8^-CD25⁺ cells by MBP/rIL-2 induced relevant antigen-specific Treg within days, which expressed CD8α, CD8β and CD62L with a Ts1 phenotype and that had greater potency than freshly isolated antigen naive CD4⁺CD25⁺Treg in suppressing clinical severity of EAE and immune inflammation in CNS. These findings may guide development of antigen-specific Treg for therapy.