title: Probing the effector and suppressive functions of human T cell subsets using antigen-specific engineered T cell receptors.
abstract: Activation of T cells through the engagement of the T cell receptors (TCRs) with specific peptide-MHC complexes on antigen presenting cells (APCs) is the major determinant for their proliferation, differentiation and display of effector functions. To assess the role of quantity and quality of peptide-MHC presentation in eliciting T cell activation and suppression functions, we genetically engineered human T cells with two TCRs that recognize HLA-A*0201-restricted peptides derived from either HIV or melanoma antigens. The engineered-TCRs are highly functional in both CD8(+) and CD4(+) T cells as assessed by the upregulation of activation markers, induction of cytokine secretion and cytotoxicity. We further demonstrated that engineered-TCRs can also be expressed on naïve human T cells, which are stimulated through APCs presenting specific peptides to induce T cell proliferation and acquire effector functions. Furthermore, regulatory T cells (Tregs) ectopically expressing the engineered-TCRs are activated in an antigen-specific fashion and suppress T cell proliferation. In this system, the inhibitory activity of peptide-stimulated Tregs require the presence of dendritic cells (DCs) in the culture, either as presenters or as bystander cells, pointing to a critical role for DCs in suppression by Tregs. In conclusion, the engineered-TCR system reported here advances our ability to understand the differentiation pathways of naïve T cells into antigen-specific effector cells and the role of antigen-specific signaling in Treg-mediated immune suppression.
authors: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors: Qi
authors: Q
authors: Wan
authors: Lina
authors: L
authors: Kozhaya
authors: Keren
authors: K
authors: Imberg
authors: Frances
authors: F
authors: Mercer
authors: Shi
authors: S
authors: Zhong
authors: Michelle
authors: M
authors: Krogsgaard
authors: Derya
authors: D
authors: Unutmaz
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000276:immunology; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
chemical_list: D000939:Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell