Autoregulatory CD8 T-Cells Modulate CNS Autoimmune Disease by Targeting Encephalitogenic CD4 T-Cells

dc.contributor.advisorKarandikar, Nitin J.en
dc.creatorOrtega, Sterling Bolivaren
dc.description.abstractMultiple Sclerosis (MS) is a disease, which presents with neurological dysfunction and is believed to have an immunological etiology. Lesions in the central nervous system (CNS) are characterized by an inflammatory cellular infiltration and demyelination of neuronal axons. It is believed that myelin sheath-targeting CD4 T-cells are important mediators of this disease. While it is known that CD8 T-cells are present, oligoclonally expanded and are the predominant T-cell population in the MS CNS lesion, their antigen specificity and function remains to be elucidated. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we are currently evaluating the role of these poorly studied myelin antigen-specific CD8 T-cells in the context of this autoimmune disease. We have observed that myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅)-specific CD8 T-cells do not mediate EAE, but in fact are capable of suppressing both de novo and established clinical disease. Corroborating these data, CD8-/- C57BL/6 mice are now shown to exhibit a more severe EAE. However, the characterization, mechanism of action and cellular targets of these autoreactive regulatory CD8 T-cells are still unknown. Initial observations revealed that disease ameliorating CD8 T-cells are not unique to MOG₃₅₋₅₅-induced EAE, as proteolipid protein peptide (PLP₁₇₈₋₁₉₁)-induced EAE in B6 and SJL mice strains were capable of generating disease ameliorating CNS antigen-specific CD8 T-cells. Autoreactive regulatory (autoregulatory) CD8 T-cells exhibit a central memory phenotype (CCR7+CD62L+CD44-) and produce IFN-γ and perforin. Disease suppression by these cells is dependent on recognition of cognate antigen in vivo within the context of MHC Class Ia. These cells do not traffic to the CNS upon transfer into naïve mice; however, they gain CNS access following induction of CNS inflammation, suggesting both a peripheral immune compartment and CNS mechanism of action. Interestingly, autoregulatory CD8 T-cell-mediated suppression is IFN-γ and perforin-dependent and can be augmented by IL-12 in vitro modulation. Next, we asked whether autoregulatory CD8 T-cells could directly target encephalitogenic myelin-specific CD4 T-cells. We now report that treatment with myelinspecific CD8 T-cells results in significantly attenuated adoptive (CD4 T-cell mediated) EAE. Moreover, increased disease severity in CD8-/- mice correlated with an increase in autoreactivity and inflammatory cytokine production by myelin-specific CD4 T-cells. This is reversible upon adoptive transfer of MOG₃₅₋₅₅-specific CD8 T-cells. Targeting of encephalitogenic CD4 T-cells by myelin-specific CD8 T-cells is sufficient, as induction of wildtype adoptive EAE in KᵇDᵇ-/- recipient mice could be suppressed. In vivo proliferation assays revealed a global suppression/cytotoxicity of MOG-specific CD4 T-cells. These studies define the immune regulatory function of autoreactive CD8 T-cells in EAE. Our results demonstrate that autoregulatory CD8 T-cells have an important disease ameliorating role in EAE, which is a disease of perturbed immune regulation. Understanding this arm of the adaptive immune system offers a promising strategy for immunotherapeutic intervention of MS.en
dc.subjectCD4-Positive T-Lymphocytesen
dc.subjectCD8-Positive T-Lymphocytesen
dc.subjectMultiple Sclerosisen
dc.titleAutoregulatory CD8 T-Cells Modulate CNS Autoimmune Disease by Targeting Encephalitogenic CD4 T-Cellsen
dc.type.materialTexten School of Biomedical Sciencesen Biologyen Southwestern Medical Centeren of Philosophyen


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