Cross-competition shapes CD8+ T cell hierarchies and differentiation after RNA vaccination

作者：Mark O. McCarron, Milena Hornburg, Thomas D. Wu, Ann-Jay Tong, Siri Tähtinen, Martine Darwish, Emily Freund, Ying Feng, David Eisel, Camille-Charlotte Balança, Itai Doron, Huan Lan, Sophie M. Lehar, Tamaki Nozawa, Yoko Oei, Vincent Javinal, Armando Navarro, Yajun Chestnut, Alan Gutierrez, Sara Wichner, Cecile de la Cruz, Benjamin Haley, Craig Blanchette, Mathias Vormehr, Lena M. Kranz, Uğur Şahin, Ira Mellman, Jill Schartner, Lélia Delamarre · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.10.26.684631 · 被引用次数：5 · 研究领域：T-cell and B-cell Immunology

Short Summary Immunodominance is a universal feature of adaptive immunity that constrains T cell expansion, clonal diversity and breadth resulting in a narrowly focused T cell response. While observed across diverse priming settings and vaccine platforms, the influence of immunodominance on T cell phenotype remains unclear. Using an mRNA lipoplex vaccine encoding multiple antigens to study how immunodominance influences CD8+ T cell fate, we found that dominant CD8+ T cell responses alter the magnitude and phenotype of subdominant responses through peptide-MHC-I stability-mediated T cell cross-competition. Dominant CD8+ T cell responses preferentially acquired markers associated with terminal differentiation and cytotoxic function, while sub-dominant responses adopted memory-precursor and stem-like features. Removal of dominant responses allowed increased expansion of sub-dominant T cell responses and adoption of terminally differentiated effector phenotypes. These findings reveal that immunodominance dynamically shapes the magnitude, breadth and differentiation of CD8+ T cell responses and highlights opportunities to fine-tune T cell responses for therapeutic vaccination.