Costimulation Blockade in Combination with IL-2 Permits Regulatory T Cell Sparing Immunomodulation That Inhibits Autoimmunity

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Nov 8

PMID 36347877

Authors

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

Lucy S K Walker

Affiliations

Soon will be listed here.

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.

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