JCI Insight (Nov 2022)

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

  • 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

Journal volume & issue
Vol. 7, no. 22

Abstract

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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.

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