178: Characterization of PD-1+Tim-3+ ‘Exhausted’ CD8 T cells in mouse models of systemic lupus erythematosus

2013 
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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