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.
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Data availability
The data supporting the findings of this study are available within the paper and its supplementary information files. Source data are provided with this paper.
Code availability
The computer code used in the study is available from the corresponding author upon request.
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Acknowledgements
This work was funded by Diabetes UK, MedImmune (now AstraZeneca), the Medical Research Council and the Rosetrees Trust. The authors received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant no. 675395. Diabetes research in the Walker laboratory is supported by Type One Mission. We acknowledge the support of the Type 1 Diabetes TrialNet study group, which identified study participants and provided samples and follow-up data for this study. The Type 1 Diabetes TrialNet study group is a clinical trial network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the cooperative agreement nos. U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509 and the Juvenile Diabetes Research Foundation (JDRF). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or JDRF. We thank A. Pesenacker for helpful comments on the manuscript.
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Contributions
N.M.E. performed the experiments, analyzed the data, prepared the figures and cowrote the manuscript. F.H. performed the experiments, analyzed the data and edited the manuscript. N.T. performed the predictive modeling, prepared the figures and cowrote the manuscript. C.J.W., L.P., R.K., A.K., V.O., E.M.R., E.N., Y.E., M.E. and R.B. assisted with the experiments and edited the manuscript. P.A. and L.J. provided expertise and funding. M.P. provided expertise and facilitated sample sharing. M.R. provided expertise and was the coapplicant for funding. L.S.K.W. conceptualized and supervised the study, applied for funding and wrote the manuscript.
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AstraZeneca contributed to the funding of the study. P.A. and L.J. declare an interest in developing costimulation blockade reagents at AstraZeneca. L.S.K.W. and N.T. are inventors on a patent application related to these findings.
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Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Edner, N.M., Heuts, F., Thomas, N. et al. Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes. Nat Immunol 21, 1244–1255 (2020). https://doi.org/10.1038/s41590-020-0744-z
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DOI: https://doi.org/10.1038/s41590-020-0744-z
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