TScan-II: A genome-scale platform for the de novo identification of CD4+ T cell epitopes

作者：Mohammad Haj Dezfulian, Tomasz Kula, Thomas J. F. Pranzatelli, Nolan Kamitaki, Qingda Meng, Bhuwan Khatri, Paola Pérez, Qikai Xu, Aiquan Chang, Ayano C. Kohlgruber, Yumei Leng, Ananth Aditya Jupudi, Michelle L. Joachims, John A. Chiorini, Christopher J. Lessard, Amy Darise Farris, Senthil K. Muthuswamy, Blake M. Warner, Stephen J. Elledge · 发表于：Cell · 年份：2023 · DOI：10.1016/j.cell.2023.10.024 · 被引用次数：56 · 研究领域：Immunotherapy and Immune Responses、T-cell and B-cell Immunology、Immune Cell Function and Interaction

CD4 + T cells play fundamental roles in orchestrating immune responses and tissue homeostasis. However, our inability to associate peptide human leukocyte antigen class-II (HLA-II) complexes with their cognate T cell receptors (TCRs) in an unbiased manner has hampered our understanding of CD4 + T cell function and role in pathologies. Here, we introduce TScan-II, a highly sensitive genome-scale CD4 + antigen discovery platform. This platform seamlessly integrates the endogenous HLA-II antigen-processing machinery in synthetic antigen-presenting cells and TCR signaling in T cells, enabling the simultaneous screening of multiple HLAs and TCRs. Leveraging genome-scale human, virome, and epitope mutagenesis libraries, TScan-II facilitates de novo antigen discovery and deep exploration of TCR specificity. We demonstrate TScan-II's potential for basic and translational research by identifying a non-canonical antigen for a cancer-reactive CD4 + T cell clone. Additionally, we identified two antigens for clonally expanded CD4 + T cells in Sjögren's disease, which bind distinct HLAs and are expressed in HLA-II-positive ductal cells within affected salivary glands.