Exhaustion of cytotoxic T cells during adoptive immunotherapy of virus carrier mice can be prevented by B cells or CD4+ T cells

Rapid disappearance of antiviral CTL after transfusion into persistently infected individuals is a serious limitation of adoptive immunotherapy protocols. In the mouse model of persistent infection with lymphocytic choriomeningitis virus (LCMV) naive or immune virus-specific donor CD8+ T cells are exhausted after transfusion into carrier recipients with similar kinetics. Here we show that cotransfusion of immune CD4+ T cells prevents exhaustion of immune CD8+ T cells. Interestingly, cotransfer of primed B cells also prevented CD8+ T cell exhaustion in carriers even in the absence of T helper cells. This effect required the presence of immune B cells as repetitive treatment with hyperimmune serum led to the generation of antibody escape mutants. A combination of primed CD4+ T cells and primed B cells enhanced antiviral effects and prevented exhaustion also of naive CD8+ T cells. One key factor for prevention of CD8+ T cell exhaustion was the antiviral effect of the cotransfused cells thus reducing the time that CD8+ T cells are confronted with a high systemic viral load. These findings have implications for improving adoptive immunotherapy for persistent human viral infections.