Research
EAE: Modeling CD8 function
Experimental auotimmune encephalomyelitis (EAE) is a well established animal model for multiple sclerosis that can be induced in mice by immunization with myelin antigens or by the adoptive transfer of T cells specific for myelin antigens. A great deal of our understanding about the immunologic processes that underlie MS is derived from studies in EAE. However, the vast majority of studies in MS and EAE have focused on the role of CD4+ T cells in these diseases, with the underlying assumption that MS, like classic EAE, is a CD4+ Th1/Th17-mediated autoimmune disease. As a result, most therapeutic strategies (both in the pre-clinical and clinical stages) are being focused on modulating CD4+ T cells with limited success.
Recent studies from our laboratory as well as reports from others have provided evidence for the involvement of CD8+ T cells in the pathogenesis and/or immune regulation of MS. The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. While it is known that CD8+ T cells represent the predominant T cell in an MS lesion and are oligoclonally expanded at the site of pathology, the antigenic specificity of these cells and their role is not known. There is high prevalence of CNS-specific CD8+ T cells in MS patients as well as multiple models of EAE. While it makes intuitive sense that a CNS-targeted, MHC Class I-restricted CD8+ T cell response would likely have a pathogenic role in disease, our recent studies have generated the first evidence for a novel and unexpected regulatory role for neuroantigen-specific CD8+ T cells in EAE. We thus hypothesize that CNS-specific CD8+ T cells form an important arm of intrinsic immune regulation during autoimmune demyelinating disease. We propose that this natural process can be harnessed for the development of an effective immunotherapeutic strategy. Through ongoing experiments, we will address the mechanisms of immune modulation by CNS-reactive CD8+ T cells, delineating their cellular, molecular and trafficking requirements. Moreover, the most potent immune suppressive subset of this population will be defined with the goal of developing a novel immunotherapeutic approaches
In addition to autoreactive CD8+ T-cells, we are also interested in modeling and studying Copaxone-induced (and intrinsic) regulatory CD8+ T-cells in EAE. In fact, our recent experiments demonstrate that Copaxone-induced CD8+ T cell responses are not unique to human beings: Copaxone treatment also induces CD8+ T cell responses in mice. Moreover, we have observed that CD8+ T cells are required for the in vivo efficacy of Copaxone therapy in EAE. Thus, the murine model now provides us with an ideal system in which the regulatory role of these responses can be directly addressed at a fundamental level.
Learn more
York, N., Mendoza, J., Ortega, S., Benagh, A., Tyler, A., Firan, M., Karandikar, N. (2010) Immune regulatory CNS-reactive CD8+ T cells in experimental autoimmune encephalomyelitis. J Autoimmun. 35(1): 33–44.