Suppression of inducible CD4 regulatory cells by MHC class I-restricted human tumor epitope specific TCR engineered multifunctional CD4 T cells.
Regulatory T cells (Treg) can interfere with the generation and function of anti-tumor immune effectors. Accordingly, ways that could block Treg function would be useful in cancer immunotherapy. We have previously shown that incorporation of CD4+CD25-ve T cells in an in vitro cytolytic T lymphocyte (CTL) generation assay leads to generation of induced regulatory T cells (iTregs), and that these iTreg block the generation of productive CTL response (Chattopadhyay et al., 2006). We here show that human CD4 T cells engineered to express MHC class I-restricted human melanoma associated epitope, MART-127-35, specific T cell receptor (TCR), that can simultaneously exhibit helper as well as cytolytic effector functions (Chhabra et al., 2008, Ray et al., 2010), can interfere with the generation of inducible Treg, block iTreg-mediated suppression, and allow the activation and expansion of MART-127-35 specific CTL responses, in vitro. We also show that mitigation of Treg generation by TCR engineered CD4 T cells is not mediated by a soluble factor and may involve "licensing/conditioning" of the dendritic cells (DC). Our data offer novel insights on the biology of MHC class I restricted TCReng CD4 T cells and have translational implications.
Department of Medicine, University of Connecticut Health Center, Farmington, CT, United States. Electronic address: chhabra@uchc.edu.
Arvind
A
Chhabra
Department of Medicine, University of Connecticut Health Center, Farmington, CT, United States.
Bijay
B
Mukherji
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D005818:Genetic Engineering; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007165:Immunosuppression Therapy; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D019139:Tumor Escape
D000939:Epitopes; D015395:Histocompatibility Antigens Class I; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell
MHC class I restricted CD4 T cells; Melanoma; Regulatory T cells (Treg); TCR engineered T cells