Regulation of the CD8+ T cell response to persistent polyoma virus infection.

摘要

Continuous surveillance by CD8+ T cells is essential for keeping persistent virus infections in check. How low-level persistent infection impacts the function and phenotype of polyoma virus (PyV)-specific CD8 + T cells has not been extensively examined. We identified several epitopes that are recognized by PyV-specific CD8+ T cells in B6 mice, and found variability between epitope-specific CD8+ T cell responses in their kinetics of expansion and contraction, maintenance during persistent infection, and expression of cytokine receptors and cytokine profiles. We used a novel bone marrow chimera model to demonstrate that PyV-specific CD8+ T cells are continuously primed during persistent infection.; The requirement for costimulation in antiviral CD8+ T cell responses has been actively investigated for acutely resolved viral infections, but is less defined for CD8+ T cell responses to persistent virus infection. Costimulation blockade or gene knockout of either CD28 or CD40L substantially dampened the magnitude of the acute CD8+ T cell response; simultaneous CD28 and CD40L blockade severely depressed the acute T cell response. Interestingly, we found that CD28 and CD40L costimulation is dispensable for generating and/or maintaining PyV-specific CD8+ T cells during persistent infection. However, blockade of CD27 and CD28 costimulation in persistently infected mice caused a reduction in PyV-specific CD8+ T cells. Taken together, these data indicate that CD8 + T cells primed within the distinct microenvironments of acute versus persistent virus infection differ in their costimulation requirements.; Given that PyV-specific CD8+ T cells are primed during persistent infection, we investigated whether CD4+ T cell help provided at the onset of infection and/or during persistent infection is necessary for maintaining the antiviral CD8+ T cell response. We found that antiviral CD8+ T cells in B6 and C3H mice differed in their dependence on CD4+ T cell help during acute infection. PyV-specific CD8+ T cell responses waned during persistent infection without CD4+ T cell help, although functionality was sustained. CD40 stimulation provided during T cell priming partially corrected the defect of helpless CD8+ T cells. We conclude that CD4 + T cell help is necessary to maintain the ongoing CD8+ T cell response during persistent PyV infection.