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

• DOI: 10.1038/s41467-022-34477-1
• Publication Date: 2022-11-09T04:29:15Z
• 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
• Keywords: 0303 health sciences; Interleukins; Science; Q; Autoimmunity; Regulatory T cells; Lymphocyte Activation; T-Lymphocytes, Regulatory; Article; 3. Good health; Abatacept; Immunomodulation; 03 medical and health sciences; CD28 Antigens; Peripheral tolerance; Interleukin-2; CTLA-4 Antigen; Immunosuppression

AbstractBlockade 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.