A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity
Diana Rasoulouniriana, … , Peleg Rider, Yaron Carmi
Diana Rasoulouniriana, … , Peleg Rider, Yaron Carmi
Published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4151-4164. https://doi.org/10.1172/JCI127590.
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Research Article Immunology Therapeutics

A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity

Abstract

While a high frequency of Th1 cells in tumors is associated with improved cancer prognosis, this benefit has been attributed mainly to support of cytotoxic activity of CD8+ T cells. By attempting to potentiate antibody-driven immunity, we found a remarkable synergy between CD4+ T cells and tumor-binding antibodies. This surprising synergy was mediated by a small subset of tumor-infiltrating CD4+ T cells that express the high-affinity Fcγ receptor for IgG (FcγRI) in both mouse and human patients. These cells efficiently lyse tumor cells coated with antibodies through concomitant crosslinking of their T cell receptor (TCR) and FcγRI. By expressing FcγRI and its signaling chain in conventional CD4+ T cells, we successfully employed this mechanism to treat established solid cancers. Overall, this discovery sheds new light on the biology of this T cell subset, their function during tumor immunity, and the means to utilize their unique killing signals in immunotherapy.

Authors

Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Yariv Wine, Corey Saperia, Lior Tal, Haim Gutman, Alexander Tsivian, Ronen Brenner, Eiman Abu Bandora, Nathan E. Reticker-Flynn, Peleg Rider, Yaron Carmi

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Figure 4

Naturally occurring FcγRI+-expressing CD4+ T cells lyse tumor cells coated with IgG.

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Naturally occurring FcγRI+-expressing CD4+ T cells lyse tumor cells coat...
(A) Mean percentages of FcγR-expressing CD4+ T cells in different organs from naive mice. (B) Confocal microscopy of spleen sections from naive mice. (C) Intracellular staining of T-bet and RORγT in naive spleen and tumor-infiltrating CD4+ T cells. (D) FACS-sorting strategy for FcγRIneg and FcγRIpos CD4+ T cells from naive spleens. (E) Agarose gel (1%) electrophoresis of FcγRI PCR products performed on cDNA from sorted splenic CD4+ T cells. (F) Confocal microscopy staining of sorted FcγRIneg and FcγRIpos CD4+ T cells. (G) Confocal microscopy of CD4+ T cells from WT and OT-II mice incubated for 48 hours with wasabi-labeled B16 cells, with or without antibodies against TRP1 and ovalbumin. Original magnification, ×400. (H) Viability (measured by fluorescent intensity of wasabi) of B16F10 cells after 48 hours coculture with CD4+ T cells (n = 6). Data represent mean ± SEM, and results are from 1 representative experiment out of at least 3 performed. Statistical significance was determined by 1-way ANOVA with Tukey’s post hoc test. *P < 0.05; **P < 0.01. P < 0.05 was considered significant.