Kao Kevin S, Pihlstrom Nicole L, Niejadlik Emily G, Cantaert Tineke, Ahmed Rafi, Ravetch Jeffrey V, Bournazos Stylianos
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.
Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh 120210, Cambodia.
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2509016122. doi: 10.1073/pnas.2509016122. Epub 2025 Jul 1.
A critical component of the function of IgG antibodies is their capacity to engage specialized cellular receptors, Fcγ receptors (FcγRs), expressed on effector leukocytes. Highlighting the importance of FcγR-mediated signaling in the regulation of the fate, activation, and differentiation status of leukocytes, FcγRs are ubiquitously expressed by nearly all leukocyte populations. Here, we report that while at steady state, T cells are negative for all classes of FcγRs, CD8 T cells specifically induce the expression of the activating FcγR, FcγRIIIa, in response to viral infection in cohorts of COVID-19 and dengue patients, as well as in virus infection models using FcγR humanized mouse strains. In in vivo mechanistic studies, we demonstrate that induction of FcγRIIIa 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, FcγRIIIa 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 FcγRIIIa 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.
IgG抗体功能的一个关键组成部分是其与效应白细胞上表达的特异性细胞受体——Fcγ受体（FcγRs）结合的能力。FcγRs几乎在所有白细胞群体中普遍表达，这突出了FcγR介导的信号传导在调节白细胞命运、激活和分化状态方面的重要性。在此，我们报告，在稳态下，T细胞对所有类型的FcγRs均呈阴性，但在COVID-19和登革热患者群体以及使用FcγR人源化小鼠品系的病毒感染模型中，CD8 T细胞在病毒感染后会特异性诱导激活型FcγR即FcγRIIIa的表达。在体内机制研究中，我们证明效应性CD8 T细胞上FcγRIIIa表达的诱导遵循明确的轨迹，紧密跟踪免疫反应的进程和强度，而免疫消退的特征是受体下调。对于这些CD8 T细胞而言，独特的是，单独的FcγRIIIa交联反常地不足以引发T细胞激活和细胞毒性。然而，当与T细胞受体（TCR）刺激相结合时，它会导致协同的细胞激活，并补偿终末效应性CD8 T细胞上经典共刺激分子的下调。这些结果揭示了FcγRIIIa作为一种独特的共刺激分子的先前未被认识的作用，它与TCR信号协同作用以降低CD8 T细胞激活所需的有效阈值，突出了病毒诱导抗体在调节CD8效应细胞反应中的作用。
