HLA-A2.1-restricted T cells react to SEREX-defined tumor antigen CML66L and are suppressed by CD4+CD25+ regulatory T cells.
The question of whether T cell responses to SEREX-defined tumor antigens are under regulation of naturally occurring CD4+CD25+ regulatory T cells (nTreg cells) has not been answered. To address this issue, we first identified an HLA-A2.1-restricted T cell antigen epitope of SEREX-identified tumor antigen CML66L, 66Pa. The HLA-A2.1/66Pa peptide complex in vitro stimulated the in vivo-primed T cells as shown by increased T cell proliferation, higher secretion of the T cell cytokine interferon-gamma (IFN-gamma), increased production of intracellular IFN-gamma in CD8+ T cells, and higher T cell-mediated cytotoxicities of CML66L+ human tumor cells. This suggests that CML66L elicits T cell immune responses. We also developed a novel internal reference epitope for identification of T cell epitopes by construction of chimeric CML66L containing myeloid antigen proteinase 3 epitope Pr1 as a control. Finally, we found that nTreg cells regulates T cell responses to 66Pa, and that depletion of nTreg cells via a pro-apoptotic protein Bax-dependent mechanism enhances polyclonal T cell responses to 66Pa. These findings provide new insights into the T cell participation in SEREX-defined anti-tumor immune responses and novel direction in enhancement of anti-leukemia immunotherapy by modulation of homeostasis of nTreg cells.
Yan
Y
Y
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Chen
Y
Y
Yang
F
F
Chen
I H
IH
Xiong
Z
Z
Wang
J
J
Lachman
L B
LB
Wang
H
H
Yang
X-F
XF
D000818:Animals; D000941:Antigens / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000502:physiology*; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014162:Transfection; D019444:Vaccines, DNA; D051028:bcl-2-Associated X Protein / Q000502:physiology
D000941:Antigens; D000951:Antigens, Neoplasm; D000939:Epitopes; D015789:HLA-A2 Antigen; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; C431278:NUDCD1 protein, human; D010455:Peptides; D019444:Vaccines, DNA; D051028:bcl-2-Associated X Protein; D007371:Interferon-gamma