Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Abstract

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-gamma) 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. IMPORTANCE Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) that they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T cells, called helper T cells, is required.