Open AccessAn IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice
Author(s) -
Liliane Khoryati,
Minh N. Pham,
McKenna Sherve,
Swarnima Kumari,
Kevin D. Cook,
Josh T. Pearson,
Marika Bogdani,
Daniel Campbell,
Marc A. Gavin
Publication year - 2020
Publication title -
science immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.83
H-Index - 51
ISSN - 2470-9468
DOI - 10.1126/sciimmunol.aba5264
Subject(s) - autoimmunity , nod mice , immunology , il 2 receptor , receptor , effector , agonist , regulatory t cell , biology , nod , microbiology and biotechnology , t cell , chemistry , immune system , endocrinology , diabetes mellitus , biochemistry
Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (T reg ) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved T reg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced T reg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective T reg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall T reg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential T reg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of T reg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.