CNS-specific autoregulatory CD8 T cells rely on IFNγ signaling for optimal suppression of pathogenic CD4 T cell responses during inhibition of demyelinating disease

Abstract

Abstract Investigating the complex cellular interplay controlling immunopathogenic and immunoregulatory responses is critical for understanding multiple sclerosis (MS) pathogenesis and for developing successful immunotherapies for patients. We have shown previously that CNS-specific CD8 T cells (CNS-CD8) have an unexpected regulatory role in the MS mouse model experimental autoimmune encephalomyelitis (EAE). CNS-CD8 fail to transfer or exacerbate disease but rather protect mice from EAE, and use IFNγ and perforin production to exert suppression. However, the cellular target and downstream effects of IFNγ are less well understood. Here, we evaluated IFNγ dynamics, its receptor and perforin during inhibition of CNS-specific DTH and EAE and show that both IFNγ and perforin production by CNS-CD8 were required at different times to suppress CD4 responses and inhibit EAE disease. Interestingly, while WT CNS-CD8 suppressed CD4 responses in IFNγR-deficient mice, IFNγR-deficient CD8 T cells showed suboptimal inhibition of CD4 responses in WT mice. Likewise, IFNγR-deficient CD8 T cells also exhibited delayed and suboptimal EAE suppression. These data suggest that autoregulatory CD8 T cells’ ability to suppress pathogenic responses during demyelinating disease is influenced by different mechanisms during different phases of disease. Moreover, the results suggest that IFNγ may have an effect on the CD8 T cells themselves, revealing a potential previously unappreciated autocrine/paracrine IFNγ-mediated pathway. Results from these studies have mechanistic implications for the interaction between IFNγ-mediated and perforin-mediated suppression pathways, which may help educate future adoptive immunotherapeutic approaches for MS.