CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells.

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.

• Authors: Ziqiang Zhu, Steven M Cuss, Vinod Singh, Devikala Gurusamy, Jennifer L Shoe, Robert Leighty, Vincenzo Bronte, Arthur A Hurwitz
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 7 Pg. 3482-9 (Oct 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26320256 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Antigens, Neoplasm
• Epitopes, T-Lymphocyte

Topics

• Animals
• Antibody Affinity (genetics, immunology)
• Antigens, Neoplasm (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Cytotoxicity, Immunologic (immunology)
• Dendritic Cells (immunology)
• Epitopes, T-Lymphocyte (immunology)
• Immune Tolerance (immunology)
• Lymphocyte Activation (immunology)
• Melanoma (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic