CD48 is an adhesion and costimulatory molecule expressed constitutively on nearly all hematopoietic cells. Via interactions with its ligand CD2, it contributes to synapse organization between T cells and APCs, and can enhance TCR signaling; via interactions with its higher affinity ligand CD244, CD48 mediates interactions with T cells and NK cells. In addition to its roles in T cell activation and NK-mediated lysis, CD48 deficiency is associated with development of spontaneous lupus-like disease on a mixed 129 and B6 genetic background, but not on a mixed 129 and Balb/c background. Despite these cellular and clinical observations, the mechanisms by which CD48 might contribute to autoimmunity and tolerance in vivo were not well defined. In this thesis we examined the immunoregulatory roles of CD48 in spontaneous and induced models of autoimmune disease, using CD48 deficient mouse strains and anti-CD48 antibodies. We found that CD48 deficiency did not precipitate spontaneous lupus-like disease in mice on a pure B6 background, but resulted in a spontaneous increase in lymphocyte activation within both young and aged mice. This implicated neighboring immunoreceptor genes in development of lupus-like disease. CD48 deficient mice had modestly attenuated disease in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), including reduced severity and accelerated resolution. At the peak of disease, CNS-infiltrating CD4+ T cells in CD48 deficient mice produced less GM-CSF, a cytokine that contributes to encephalitogenicity of T cells in EAE. When we examined CD48 expression in wild type mice during EAE, we found that CD48 expression was increased on activated CD4+ T cells, and that CD48++ CD4+ T cells were enriched for GM-CSF, IL-17A and IFNγ-producing cells. Administration of anti-CD48 antibody during EAE in wild type mice dramatically reduced the number of these cytokine-producing cells, and could significantly attenuate or even prevent disease. Anti-CD48-mediated attenuation of EAE was partially dependent on Fc receptors, suggesting a mechanism of depletion of activated CD48++ CD4+ T effectors. Collectively, our data support a critical role for CD48 in regulating the generation of activated lymphocytes and suggest that CD48 may be used to identify pathogenic self-reactive T cells in autoimmune disease. / Medical Sciences
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/17467326 |
| Date | 02 November 2015 |
| Creators | McArdel, Shannon |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation, text |
| Format | application/pdf |
| Rights | open |
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