FcγRIIIa is a noncanonical costimulatory molecule for CD8 T cells

• 成果类型: Article
• 署名作者: Kao, Kevin S.; Pihlstrom, Nicole L.; Niejadlik, Emily G.; Cantaert, Tineke; Ahmed, Rafi; Ravetch, Jeffrey, V; Bournazos, Stylianos
• 署名单位: Rockefeller University; Pasteur Network; Institut Pasteur Cambodia; Emory University; Emory University; Emory University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10548
• DOI: 10.1073/pnas.2509016122
• 发表日期: 2025-07-01
• 关键词: neutralizing antibodies; zeta-chain; receptor; cd16; memory; exhaustion; ligation; binding; dimers; FAMILY

摘要

A critical component of the function of IgG antibodies is their capacity to engage specialized cellular receptors, Fc gamma receptors (Fc gamma Rs), expressed on effector leukocytes. Highlighting the importance of Fc gamma R-mediated signaling in the regulation of the fate, activation, and differentiation status of leukocytes, Fc gamma Rs are ubiquitously expressed by nearly all leukocyte populations. Here, we report that while at steady state, T cells are negative for all classes of Fc gamma Rs, CD8 T cells specifically induce the expression of the activating Fc gamma R, Fc gamma RIIIa, in response to viral infection in cohorts of COVID-19 and dengue patients, as well as in virus infection models using Fc gamma R humanized mouse strains. In in vivo mechanistic studies, we demonstrate that induction of Fc gamma RIIIa expression on effector CD8 T cells follows a well-defined trajectory that closely tracks the course and magnitude of the immune response, while immune resolution is characterized by receptor downregulation. Uniquely to these CD8 T cells, Fc gamma RIIIa crosslinking alone is paradoxically insufficient to elicit T cell activation and cytotoxicity. However, when coupled with T cell receptor (TCR) stimulation, it results in synergistic cellular activation and, compensates for the downregulation of canonical costimulatory molecules on terminal effector CD8 T cells. These results reveal a previously unappreciated role for Fc gamma RIIIa as a unique costimulatory molecule that synergizes with TCR signaling to lower the effective threshold required for CD8 T cell activation, highlighting the role of virally induced antibodies in modulating CD8 effector cell responses.