Ignorance, exhaustion and death: T cell function during chronic viral infection

T cell responses during viral infection involve the activation and expansion of a limited number of virus-specific precursors, resulting in an effector population. We have estimated the number of naive virus-specific CD8 T cells in mice by titration of a known quantity of TCR transgenic cells and measuring the relative contribution of endogenous and donor cells during infection with LCMV. Following clearance of virus, the majority of effector T cells undergo apoptosis leaving behind a stable pool of memory cells capable of responding to subsequent infection with enhanced kinetics due to both quantitative and qualitative changes. We have examined the selection of memory cells both in terms of epitope-specific hierarchy as well as the TCR repertoire within epitope-specific populations. In addition, we have analyzed how these parameters change during recall responses.; During chronic viral infection, we show that virus-specific T cell responses wane due to clonal deletion or functional exhaustion of epitope-specific populations. The repertoire and affinity of epitope-specific cells that persist during chronic infection are similar to those capable of controlling infection. Generation of functionally exhausted CD8 T cells is dependent upon persistence of wt virus. In mice that select for viral CTL escape variants that abrogate epitope presentation, virus-specific T cells maintain functional responsiveness despite high viremia. However, the fate of virus-specific T cells recognizing non-mutated epitopes remains unchanged, as these cells become functionally exhausted or are deleted.; We have also investigated therapeutic approaches to enhance anti-viral T cell responses in vivo. IL-2 therapy did not enhance the generation of virus-specific CD8 T cell responses and was detrimental to the generation of virus-specific CD4 T cell responses. However, IL-2 was effective at prolonging T cell responses in acutely infected mice. In addition, IL-2 promoted memory T cell proliferation, challenging the notion that IL-2 is detrimental to the maintenance of memory T cells in vivo. IL-2 therapy was toxic to mice infected with virulent strains of LCMV during the acute phase of the T cell response. However, IL-2 administered following this period was effective in enhancing the magnitude of virus-specific CD8 and CD4 T cell responses in vivo.