Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire.

Abstract

CD4(+) regulatory T cells (Tregs) accumulate at tumor sites and play a critical role in the suppression of immune responses against tumor cells. In this study, we show that two immunodominant epitopes derived from the tumor Ags (TAs) NY-ESO-1 and TRAG-3 stimulate both CD4+ Th cells and Tregs. TA-specific Tregs inhibit the proliferation of allogenic T cells, act in a cell-to-cell contact dependent fashion and require activation to suppress IL-2 secretion by T cells. TRAG-3 and NY-ESO-1-specific Tregs exhibit either a Th1-, a Th2-, or a Th0-type cytokine profile and dot not produce IL-10 or TGF-beta. The Foxp3 levels vary from one Treg clone to another and are significantly lower than those of CD4+CD25high Tregs. In contrast to NY-ESO-1-specific Th cells, the NY-ESO-1-specific and TRAG-3-specific Treg clonotypes share a common TCR CDR3 Vbeta usage with Foxp3+CD4+CD25high and CD4+CD25- T cells and were not detectable in PBLs of other melanoma patients and of healthy donors, suggesting that their recruitment occurs through the peripheral conversion of CD4+CD25- T cells upon chronic Ag exposure. Collectively, our findings demonstrate that the same epitopes spontaneously stimulate both Th cells and Tregs in patients with advanced melanoma. They also suggest that TA-specific Treg expansion may be better impaired by therapies aimed at depleting CD4+CD25high Tregs and preventing the peripheral conversion of CD4+CD25- T cells.

• Authors: Julien Fourcade, Zhaojun Sun, Pavol Kudela, Bratislav Janjic, John M Kirkwood, Talal El-Hafnawy, Hassane M Zarour
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 12 Pg. 6709-18 (Jun 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20483736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Neoplasm
• Epitopes, T-Lymphocyte
• Receptors, Antigen, T-Cell

Topics

• Antigens, Neoplasm (immunology)
• Cell Separation
• Epitopes, T-Lymphocyte (immunology)
• Flow Cytometry
• Humans
• Lymphocyte Activation (immunology)
• Melanoma (immunology)
• Receptors, Antigen, T-Cell (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes, Helper-Inducer (immunology)
• T-Lymphocytes, Regulatory (immunology)