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Systemic lupus erythematosus is an autoimmune disorder characterized by the presence of autoantibodies and inflammation that leads to tissue damage. Whether CD8 T cells play a role in the pathogenesis of SLE is not clear. The accumulation of ‘exhausted’ CD8 T cells with impaired effector function and distinguished by co-expression of PD-1, Tim-3, and Lag-3 has been described under a number of settings including chronic viral infection, sepsis, and cancer. In the current study, we investigated the phenotype of CD8 T cells in multiple mouse models of lupus. We report an age-dependent accumulation of ‘exhausted’ CD8 T cells in multiple mouse models of lupus. The phenotype of these cells is defined by expression of PD-1, along with a substantial population of cells co-expressing PD-1 with Tim-3 and Lag-3. A similar accumulation of ‘exhausted’ CD8 T cells was found in SLE1, NZBWF 1 , Sanroque, and MRL/lpr strains and was significantly greater than that found in age-matched C57Bl/6 mice. Furthermore PD-1 + CD8 T cells were distributed throughout the body in both secondary lymphoid organs as well as a variety of tissues, such as liver and kidney. These cells exhibited altered cytokine production upon ex vivo stimulation with more cells capable of producing Granzyme B, IFN γ , and IL-10, and fewer cells producing TNF α or IL-2. Moreover, these cells exhibited impaired survival after anti-CD3/CD28 costimulation. The frequency of PD-1 + CD8 T cells showed a strong positive correlation with the frequency of GC B cells as well as PD-1 + CD4 T cells. These results suggest that ‘exhausted’ CD8 T cells may contribute to the onset or exacerbation of disease. Alternatively, impaired CD8 T cell function may be a secondary consequence of the disease that may result in increased susceptibility to pathogen infection. Future studies in human and animal models are warranted. Disclosure: all authors are employees of MedImmune. |
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