Myelin antigen-specific effector CD8 ⁺ T cells induce chronic CNS autoimmunity in a CD4 ⁺ T cell-dependent manner

Both CD4 ⁺ and CD8 ⁺ T cells play critical roles in the immunopathogenesis of multiple sclerosis (MS). 1C6 T cell receptor transgenic (TcR-Tg) mice on the nonobese diabetic (NOD) background have a MOG _[35-55]- specific, MHC class II-restricted, TcR that selects for both CD4 ⁺ and CD8 ⁺ T cells. Adoptive transfer of 1C6 CD4 ⁺ T helper 17 (Th17) cells can induce experimental autoimmune encephalomyelitis (EAE) with a progressive disease course. In the current study, we assessed the function and pathogenicity of 1C6 CD8 ⁺ T cells. We found that they proliferated and produced inflammatory cytokines in response to MOG _[35-55] peptide under both T cytotoxic 1 (Tc1) and Tc17 differentiation conditions, albeit with reduced expansion relative to their Th1 or Th17 counterparts. Both 1C6 Tc1 and Tc17 cells were able to induce EAE upon adoptive transfer to NOD. Scid mice. Intriguingly, we noted in vivo expansion of CD4 ⁺ T cells in the spleen and CNS of NOD. Scid recipients as well as in lymphocyte-sufficient animals, despite 1C6 Tc cells being purified on CD8 expression prior to transfer. Furthermore, 1C6 Tc17 cells expressed ThPOK, a master differentiation factor for CD4 ⁺ T cells. Finally, anti-CD4 ⁺ T cell blockade abrogated CD8 ⁺ T cell infiltration of the CNS and disease induction in Tc17 recipient mice. Our data provide insight into the interplay of CD4 ⁺ and CD8 ⁺ T cells in CNS autoimmunity.