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.