Antigen-experienced CD4(+) T cells limit naïve T-cell priming in response to therapeutic vaccination in vivo.
CD4(+) T cells play a central role in protective immunity. In a mouse tumor model, we previously found that tumor growth elicits natural CD4(+) T-cell responses, but impedes therapeutic vaccination. We show here that inhibition of vaccine-mediated naïve T-cell priming is due to the presence of a minor but distinct population of tumor-reactive CD4(+) T cells. These cells are generated in the tumor draining lymph nodes (LN), are capable of systemic redistribution, and act to limit the representation of antigen-bearing MHC II(+) antigen-presenting cells (APC) in contralateral LNs or when transferred to tumor-free mice. Surgical tumor resection, which lowers the representation of tumor primed CD4(+) T cells, restored to some extent vaccine-induced CD4(+) T-cell activation. Likewise, vaccination with artificial APCs (latex beads) or higher numbers of dendritic cells allowed comparable CD4(+) T-cell priming in tumor-free and tumor-bearing mice. Together, our results emphasize the ability of antigen-experienced CD4(+) T lymphocytes to interfere with therapeutic vaccination and highlight the need for alternative strategies able to surmount limitations imposed by ongoing immune responses.
Schiering
Chris
C
Program in Immunology and Bio-Immunotherapy of Cancer, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
Guarnerio
Jlenia
J
Basso
Veronica
V
Muzio
Luca
L
Mondino
Anna
A
D000230:Adenocarcinoma / Q000276:immunology* / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology; D007178:Inbreeding; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology; D017211:Treatment Failure
D000953:Antigens, Protozoan; D019496:Cancer Vaccines; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D015800:Protozoan Proteins; C093139:LACK antigen, Leishmania