IL-6–targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function
Cate Speake, … , Carla J. Greenbaum, Jane H. Buckner
Cate Speake, … , Carla J. Greenbaum, Jane H. Buckner
Published October 25, 2022
Citation Information: JCI Insight. 2022;7(22):e159436. https://doi.org/10.1172/jci.insight.159436.
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Research Article Immunology

IL-6–targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function

Abstract

Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use, yet whether the immunological effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in individuals with type 1 diabetes using anti–IL-6 (siltuximab) or anti–IL-6 receptor (IL-6R; tocilizumab) therapies and investigated the impact of this in vivo blockade on T cell fate and function. Immune outcomes were influenced by the target of the therapeutic intervention (IL-6 versus IL-6R) and by peak drug concentration. Tocilizumab reduced ICOS expression on T follicular helper cell populations and T cell receptor–driven (TCR-driven) STAT3 phosphorylation. Siltuximab reversed resistance to Treg-mediated suppression and increased TCR-driven phosphorylated STAT3 and production of IL-10, IL-21, and IL-27 by T effectors. Together, these findings indicate that the context of IL-6 blockade in vivo drives distinct T cell–intrinsic changes that may influence therapeutic outcomes.

Authors

Cate Speake, Tania Habib, Katharina Lambert, Christian Hundhausen, Sandra Lord, Matthew J. Dufort, Samuel O. Skinner, Alex Hu, MacKenzie Kinsman, Britta E. Jones, Megan D. Maerz, Megan Tatum, Anne M. Hocking, Gerald T. Nepom, Carla J. Greenbaum, Jane H. Buckner

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Figure 4

Tocilizumab and siltuximab have opposing effects on TCR-induced p-STAT3 signaling in naive CD4+ T cells.

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Tocilizumab and siltuximab have opposing effects on TCR-induced p-STAT3 ...
Enriched pan T cells from siltuximab-treated or tocilizumab-treated patients with T1D were stimulated or not with anti-CD3/anti-CD28–coated beads for 4 hours. Cells were stained for p-STAT3 and total STAT3. Each line represents an individual patient; n = 10 for siltuximab (except for F where n = 7; gated CD4+CD45RA+ naive CD4+ T cells) and n = 10 for tocilizumab (gated CD4+CD27+CD45RA+ naive CD4+ T cells). Solid circles represent d0 prior to administration of the drug, and open circles represent d14 after drug administration. (A) p-STAT3 geometric MFI (gMFI). (B) Frequency of p-STAT3+ cells. (C) p-STAT3 MFI for cohort that participated in both studies (n = 4); note these individuals are also included in A, B, E, and F. (D) Gating strategy for total STAT3 gMFI of gated naive CD4+ T cells using unstimulated enriched pan T cells: histograms for representative siltuximab-treated patient and representative tocilizumab-treated patient. (E) Total STAT3 MFI of unstimulated cells. (F) p-STAT3 MFI after stimulation with IL-10 (20 ng/mL for 30 minutes). Statistical tests: Wilcoxon matched-pairs signed-rank test.