Deciphering CD4⁺ T cell specificity using novel MHC-TCR chimeric receptors

Area of Science:

• Immunology
• Molecular Biology
• Biotechnology

Background:

• T cell antigen receptors (TCRs) bind peptide-MHC (pMHC) complexes with low affinity, complicating the identification of cognate peptides.
• Discovering natural T cell epitopes is crucial for understanding immune responses and developing targeted therapies.

Purpose of the Study:

• To develop and validate a novel platform for the discovery of MHC class II epitopes.
• To enable unbiased and efficient identification of natural CD4+ T cell epitopes and analyze TCR cross-reactivity.
• To demonstrate the utility of the platform for identifying viral, tumor-specific, and neo-antigen epitopes.

Main Methods:

• Development of a reporter cell-based screening platform using engineered pMHC-TCR (MCR) hybrid molecules.
• Screening of cDNA-derived peptides to identify cognate peptides recognized by T cells.
• Application of MCR technology in mouse models for viral and tumor immunity, and proof-of-concept in human T cells.
• Identification of immunogenic tumor neo-antigens and assessment of vaccination efficacy.

Main Results:

• The MCR platform efficiently identifies natural CD4+ T cell epitopes in an unbiased manner.
• Detailed analysis of TCR cross-reactivity patterns beyond single peptides was achieved.
• Cognate peptides for virus- and tumor-specific T cells were identified in mouse models.
• Immunogenic tumor neo-antigens were identified, and vaccination with a recognized peptide conferred protection against tumor challenge.
• Proof-of-concept for human T cell applications was established.

Conclusions:

• The MCR technology offers a powerful tool for discovering T cell epitopes and understanding TCR recognition.
• This platform facilitates the identification of personalized T cell-specific neo-antigens for potential clinical applications, including cancer immunotherapy.
• The MCR technology holds significant promise for both basic immunological research and the development of novel diagnostics and therapeutics.