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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.
Highlights
Human T cells engineered to express T cell receptors (TCRs) specific for antigens from tumors or infectious organisms have recently been developed as an effective adoptive immunotherapy [1,2,3]
We introduced the engineered-TCRs into TN cells cultured in IL-7 and showed that naıve CD8+ and CD4+ T cells cultured in IL-7 could be transduced to express the engineered-TCRs and stimulated by specific peptidepresenting antigen presenting cells (APCs) to proliferate and display antigen-specific effector functions
T cells engineered with mouse-human TCRs were shown to have higher cell surface expression and increased TCR complex stability, compared to T cells engineered with human TCRs alone, which results in an enhanced anti-tumor activity [12]
Summary
Human T cells engineered to express T cell receptors (TCRs) specific for antigens from tumors or infectious organisms have recently been developed as an effective adoptive immunotherapy [1,2,3]. Infusion of genetically reprogrammed T cells recognizing tumor antigens into patients has had reasonable success in augmenting tumor-specific immunity [1,2] and can confer some ability for tumor regression [2,3]. This engineering approach was applied to generate CD8+ T cell responses to HIV antigens as a potential therapeutic approach to eliminate virusinfected cells in patients [4,5,6]. Antigenspecific TCR-engineered naıve T (TN) cells with enhanced proliferative capacity, differentiation and better survival are needed to improve both in vivo cell therapies and vaccine formulations
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