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.


OBJECTIVE
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.
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
T W H
TW
Flinsenberg
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
L
L
Spel
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
M
M
Jansen
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
D
D
Koning
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
C
C
de Haar
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
M
M
Plantinga
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
R
R
Scholman
Laboratory of Hematology, University Medical Centre Leiden, Leiden, The Netherlands.
M M
MM
van Loenen
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
S
S
Nierkens
Bioceros BV, Utrecht, The Netherlands.
L
L
Boon
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
D
D
van Baarle
Laboratory of Hematology, University Medical Centre Leiden, Leiden, The Netherlands.
M H M
MH
Heemskerk
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
J J
JJ
Boelens
Laboratory of Translational Immunology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands mboes@umcutrecht.nl.
M
M
Boes
D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D036101:Cord Blood Stem Cell Transplantation; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D010750:Phosphoproteins / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology; D014775:Virus Activation
D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma