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.
Hunziker
Lukas
L
Institute of Experimental Immunology, Department of Pathology, University of Zurich, Zurich, Switzerland.
Klenerman
Paul
P
Zinkernagel
Rolf M
RM
Ehl
Stephan
S
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000628:therapy*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors
D016693:Receptors, Antigen, T-Cell, alpha-beta