CD4+ T cell help selectively enhances high-avidity tumor antigen-specific CD8+ T cells

Z Zhu, SM Cuss, V Singh, D Gurusamy… - The Journal of …, 2015 - journals.aai.org
Z Zhu, SM Cuss, V Singh, D Gurusamy, JL Shoe, R Leighty, V Bronte, AA Hurwitz
The Journal of Immunology, 2015journals.aai.org
Maintaining antitumor immunity remains a persistent impediment to cancer immunotherapy.
We and others have previously reported that high-avidity CD8+ T cells are more susceptible
to tolerance induction in the tumor microenvironment. In the present study, we used a novel
model where T cells derived from two independent TCR transgenic mouse lines recognize
the same melanoma antigenic epitope but differ in their avidity. We tested whether providing
CD4+ T cell help would improve T cell responsiveness as a function of effector T cell avidity …
Abstract
Maintaining antitumor immunity remains a persistent impediment to cancer immunotherapy. We and others have previously reported that high-avidity CD8+ T cells are more susceptible to tolerance induction in the tumor microenvironment. In the present study, we used a novel model where T cells derived from two independent TCR transgenic mouse lines recognize the same melanoma antigenic epitope but differ in their avidity. We tested whether providing CD4+ T cell help would improve T cell responsiveness as a function of effector T cell avidity. Interestingly, delivery of CD4+ T cell help during in vitro priming of CD8+ T cells improved cytokine secretion and lytic capacity of high-avidity T cells, but not low-avidity T cells. Consistent with this observation, copriming with CD4+ T cells improved antitumor immunity mediated by higher avidity, melanoma-specific CD8+ T cells, but not T cells with similar specificity but lower avidity. Enhanced tumor immunity was associated with improved CD8+ T cell expansion and reduced tolerization, and it was dependent on presentation of both CD4+ and CD8+ T cell epitopes by the same dendritic cell population. Our findings demonstrate that CD4+ T cell help preferentially augments high-avidity CD8+ T cells and provide important insight for understanding the requirements to elicit and maintain durable tumor immunity.
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