Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity

Chun Jing Wang, Lina Petersone, Natalie M. Edner, Frank Heuts, Vitalijs Ovcinnikovs, Elisavet Ntavli, Alexandros Kogimtzis, Astrid Fabri, Yassin Elfaki, Luke P. Houghton, Ralf J. Hosse, David A. Schubert, Andreas P. Frei, Ellen M. Ross and Lucy S. K. Walker ()
Additional contact information
Chun Jing Wang: University College London Division of Infection & Immunity
Lina Petersone: University College London Division of Infection & Immunity
Natalie M. Edner: University College London Division of Infection & Immunity
Frank Heuts: University College London Division of Infection & Immunity
Vitalijs Ovcinnikovs: University College London Division of Infection & Immunity
Elisavet Ntavli: University College London Division of Infection & Immunity
Alexandros Kogimtzis: University College London Division of Infection & Immunity
Astrid Fabri: University College London Division of Infection & Immunity
Yassin Elfaki: University College London Division of Infection & Immunity
Luke P. Houghton: University College London Division of Infection & Immunity
Ralf J. Hosse: Roche Pharma Research & Early Development (pRED)
David A. Schubert: Roche Pharma Research & Early Development (pRED)
Andreas P. Frei: Roche Pharma Research & Early Development (pRED)
Ellen M. Ross: University College London Division of Infection & Immunity
Lucy S. K. Walker: University College London Division of Infection & Immunity

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous. Here we probe the relative roles of CD28 and IL-2 in maintaining Treg. We find provision of IL-2 counteracts the regulatory T cell loss induced by costimulation blockade while minimally affecting the conventional T cell compartment. These data suggest that combining costimulation blockade with IL-2 treatment may selectively impair effector T cell responses while maintaining regulatory T cells. Using a mouse model of autoimmune diabetes, we show combined therapy supports regulatory T cell homeostasis and protects from disease. These findings are recapitulated in humanised mice using clinically relevant reagents and provide an exemplar for rational use of a second immunotherapy to offset known limitations of the first.

Date: 2022
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DOI: 10.1038/s41467-022-34477-1

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