Cognate CD4 T-cell licensing of dendritic cells heralds anti-cytomegalovirus CD8 T-cell immunity after human allogeneic umbilical cord blood transplantation

Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), lowering survival rates by approximately 25%. While antiviral treatment ameliorates viremia, complete viral control requires CD8⁺ T-cell-driven immunity. Mouse studies suggest that cognate antigen-specific CD4⁺ T-cell licensing of dendritic cells (DCs) is required to generate effective CD8⁺ T-cell responses. For humans, this was not fully understood. We here show that CD4⁺ T cells are essential for licensing of human DCs to generate effector and memory CD8⁺ T-cell immunity against CMV in CBT patients. First, we show in CBT recipients that clonal expansion of CMV-pp65-specific CD4⁺ T cells precedes the rise in CMV-pp65-specific CD8⁺ T cells. Second, the elicitation of CMV-pp65-specific CD8⁺ T cells from rare naive precursors in cord blood requires DC licensing by cognate CMV-pp65-specific CD4⁺ T cells. Finally, also CD8⁺ T-cell memory responses require CD4⁺ T-cell-mediated licensing of DCs in our system, by secretion of gamma interferon (IFN-γ) by pp65-specific CD4⁺ T cells. Together, these data show that human DCs require licensing by cognate antigen-specific CD4⁺ T cells to elicit effective CD8⁺ T-cell-mediated immunity and fight off viral reactivation in CBT patients.