Journal
IMMUNOLOGY AND CELL BIOLOGY
Volume 96, Issue 10, Pages 1035-1048Publisher
WILEY
DOI: 10.1111/imcb.12166
Keywords
FOXP3; IFN gamma; immunosurvillance; Treg cells; tumor
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Funding
- Council for Scientific and Industrial Research
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CD8(+) T-regulatory (Treg) cells are emerging as crucial components of immune system. Previous studies have reported the presence of FOXP3(+)CD8(+) Treg cells, similar to CD4(+) Tregs, in cancer patients which produce high levels of the immunosuppressive cytokines, IL10 and TGF beta. At an early stage of tumor development, we have identified a subset of FOXP3(-)CD8(+)CD25(+)KIR(+)CD127(-) Treg-like cells, which are IFN gamma(+). However, this early-induced CD8(+)CD25(+)CD127(-) T-cell subset is certainly distinct from the IFN gamma(+)CD8(+) T-effector cells. These CD8(+)CD25(+)CD127(-) T cells express other FOXP3(-)CD8(+) Treg cell signature markers, and can selectively suppress autoreactive HLA-E+ T-FH cells as well as tumor-induced CD4(+) Treg cells. In contrast to FOXP3(+)CD8(+) Tregs, this subset does not inhibit effector T-cell proliferation or their functions as they are HLA-E-. Adoptive transfer of this early-CD8(+) Treg-like subset restrained tumor growth and inhibited CD4(+) Treg generation that impedes the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4(+) Treg cells dominate the tumor-microenvironment, CD4(+) Tregs mediate the clonal deletion of these tumor-suppressive FOXP3(-)IFN gamma(+)CD8(+)CD25(+)CD127(-) T cells and ensure tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFN gamma-producing FOXP3(-)CD8(+)CD25(+)CD127(-) T-cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4(+) Treg cells while leaving the effector T-cell population unaffected. Hence, manipulating their profile can open up a new avenue in cancer immunotherapy.
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