Examination of the role of CD8+ T cells: from autoimmunity to antigen induced exhaustion

Christine M. Bucks

doi:10.17918/00000495

CD8+ T cells are critically important for host protection against intracellular pathogens. The function of CD8+ T cells following acute TCR stimulation is dramatically different than that which occurs following chronic stimulation. Based on this observation we have undertaken studies which examine the role of CD8+ T cells under two different chronic activation conditions. In the first study, we examined the role of CD8+ T cells in initiation and perpetuation of the mouse model of Rheumatoid Arthritis, collagen induced arthritis. Previous studies examining the role of CD8+ T cells in this model suggested that they were not important for disease initiation or progression. Using monoclonal antibodies to deplete CD8+T cells, we have shown that CD8+T cells do indeed have a critical role in arthritis progression and amplification. In the absence of CD8+ T cells, the collagen arthritis observed exhibited a lag in the rate of onset, was shorter in duration, and was significantly less severe than that which was observed in control mice. We observed no significant effect on the course of arthritis when CD8+ T cells were depleted after disease onset, indicating that the role of CD8+ T cells is restricted to the early stages of arthritis. The finding that CD8+ T cells had a pathogenic role in collagen arthritis, in spite of chronic inflammation and potential auto-antigen stimulation, was interesting in light of the fact that chronic stimulation during viral infection results in functional exhaustion of CD8+ T cells. To better characterize the conditions which induce CD8+ T cell exhaustion, we created a novel system of chronic antigen stimulation using murine adapted influenza virus. Using repeated intraperitoneal delivery of influenza virus we observed that chronic antigen stimulation alone, in the absence of overt inflammation, was sufficient to induce functional exhaustion of CD8+ T cells. Chronic antigen stimulated CD8+ T cells were not capable of re-expanding or producing IFN-[gamma] in response to intranasal viral re-challenge with influenza virus. This exhausted state was antigen driven as the removal of antigen allowed for full functional recovery of the virus specific population. Interestingly, the exhausted state of CD8+ T cells was maintained even when T cell inhibitory programmed death-1 (PD-1) was inhibited. The absence of signaling through TRAIL apoptosis pathway reversed the exhausted state and allowed for nearly complete recovery of proliferation and function relative to controls. Within these studies we have identified disparate roles/function of CD8+ T cells under conditions of chronic activation. In the autoimmune model of collagen arthritis, CD8+ T cells exhibited a pathogenic role, while in our second model of chronic TCR activation CD8+ T cells developed a functional exhausted phenotype. The reason for this disparity remains unknown, but suggests that the mode of chronic activation may be of critical importance in the outcome of CD8+ T cell function.

Examination of the role of CD8+ T cells: from autoimmunity to antigen induced exhaustion

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Examination of the role of CD8+ T cells: from autoimmunity to antigen induced exhaustion

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