Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes

Nat Immunol. 2020 Oct;21(10):1244-1255. doi: 10.1038/s41590-020-0744-z. | PubMed

Natalie M Edner^{1, #}, Frank Heuts^{1, #}, Niclas Thomas¹, Chun Jing Wang¹, Lina Petersone¹, Rupert Kenefeck¹, Alexandros Kogimtzis¹, Vitalijs Ovcinnikovs¹, Ellen M Ross¹, Elisavet Ntavli¹, Yassin Elfaki¹, Martin Eichmann², Roman Baptista², Philip Ambery³, Lutz Jermutus⁴, Mark Peakman², Miranda Rosenthal¹, Lucy S K Walker⁵

1. Institute of Immunity & Transplantation, University College London Division of Infection & Immunity, Royal Free Campus, London, UK.
2. Department of Immunobiology, King's College London, London, UK.
3. Late-stage Development, Cardiovascular, Renal and Metabolism , BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
4. Research and Early Development, Cardiovascular, Renal and Metabolism , BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
5. Institute of Immunity & Transplantation, University College London Division of Infection & Immunity, Royal Free Campus, London, UK. lucy.walker@ucl.ac.uk.

#Contributed equally

Abstract

Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.

Presented By Natalie Edner | ORCID iD