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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Time-sensitive inhibition of TFH cells by abatacept in immunized mice.
Fig. 2: Abatacept decreases TFH cells during an ongoing autoimmune response in mice.
Fig. 3: Abatacept decreases TFH cells in patients with new-onset T1D.
Fig. 4: Data-driven analysis reveals additional abatacept-sensitive populations in patients with T1D.
Fig. 5: ‘TPH’ and ‘ICOS+ naïve’ cells are elevated in a mouse model of diabetes and sensitive to costimulation blockade.
Fig. 6: TPH cells identified through CellCnn display marker expression consistent with a TPH profile.
Fig. 7: Baseline TFH phenotype is associated with clinical response to abatacept.
Fig. 8: Data-driven analysis identifies cell signatures linked to clinical response to abatacept.

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.

References

  1. 1.

    Blair, H. A. & Deeks, E. D. Abatacept: a review in rheumatoid arthritis. Drugs 77, 1221–1233 (2017).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Mease, P. J. et al. Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis. Ann. Rheum. Dis. 76, 1550–1558 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Brunner, H. I. et al. Subcutaneous abatacept in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase III open-label study. Arthritis Rheumatol. 70, 1144–1154 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Lenschow, D. J. et al. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J. Exp. Med. 181, 1145–1155 (1995).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Orban, T. et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412–419 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Orban, T. et al. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care 37, 1069–1075 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Kenefeck, R. et al. Follicular helper T cell signature in type 1 diabetes. J. Clin. Invest. 125, 292–303 (2015).

    PubMed  Article  Google Scholar 

  8. 8.

    Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Heit, A. et al. Vaccination establishes clonal relatives of germinal center T cells in the blood of humans. J. Exp. Med. 214, 2139–2152 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Hill, D. L. et al. The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes. J. Exp. Med. 8, 1857–1873 (2019).

    Article  CAS  Google Scholar 

  13. 13.

    Schmitt, N., Bentebibel, S.-E. & Ueno, H. Phenotype and functions of memory Tfh cells in human blood. Trends Immunol. 35, 436–442 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Sage, P. T., Alvarez, D., Godec, J., von Andrian, U. H. & Sharpe, A. H. Circulating T follicular regulatory and helper cells have memory-like properties. J. Clin. Invest. 124, 5191–5204 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Xu, X. et al. Inhibition of increased circulating Tfh cell by anti-CD20 monoclonal antibody in patients with type 1 diabetes. PLoS ONE 8, e79858 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Ferreira, R. C. et al. IL-21 production by CD4 effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients. Diabetologia 58, 781–790 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Serr, I. et al. miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity. Proc. Natl Acad. Sci. USA 113, E6659–E6668 (2016).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Viisanen, T. et al. Circulating CXCR5+PD-1+ICOS+ follicular T helper cells are increased close to the diagnosis of type 1 diabetes in children with multiple autoantibodies. Diabetes 66, 437–447 (2017).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Borriello, F. et al. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 6, 303–313 (1997).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Walker, L. S. et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXCR5-positive CD4 cells and germinal centers. J. Exp. Med. 190, 1115–1122 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Wang, C. J. et al. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc. Natl Acad. Sci. USA 112, 524–529 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Verstappen, G. M. et al. Attenuation of follicular helper T cell-dependent B cell hyperactivity by abatacept treatment in primary Sjögren’s syndrome. Arthritis Rheumatol. 69, 1850–1861 (2017).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Piantoni, S., Regola, F., Scarsi, M., Tincani, A. & Airò, P. Circulating follicular helper T cells (CD4+CXCR5+ICOS+) decrease in patients with rheumatoid arthritis treated with abatacept. Clin. Exp. Rheumatol. 36, 685 (2018).

    PubMed  Google Scholar 

  24. 24.

    Glatigny, S. et al. Abatacept targets T follicular helper and regulatory T cells, disrupting molecular pathways that regulate their proliferation and maintenance. J. Immunol. 202, 1373–1382 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Clough, L. E. et al. Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21. J. Immunol. 180, 5393–5401 (2008).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Walker, L. S., Chodos, A., Eggena, M., Dooms, H. & Abbas, A. K. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198, 249–258 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    He, J. et al. Circulating precursor CCR7loPD-1hi CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 39, 770–781 (2013).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Morita, R. et al. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108–121 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Arvaniti, E. & Claassen, M. Sensitive detection of rare disease-associated cell subsets via representation learning. Nat. Commun. 8, 14825 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Pieper, J. et al. CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients. BMC Immunol. 14, 34 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Orban, T. et al. Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline. Diabetes 63, 3449–3457 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Leete, P. et al. Differential insulitic profiles determine the extent of β-cell destruction and the age at onset of type 1 diabetes. Diabetes 65, 1362–1369 (2016).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Breiman, L. Arcing the Edge. Technical Report 486 (Univ. California, Berkeley, 1997).

  35. 35.

    Friedman, J. H. Greedy function approximation: a gradient boosting machine. Ann. Stat. 29, 1189–1232 (2001).

    Article  Google Scholar 

  36. 36.

    Xu, H. et al. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 496, 523–527 (2013).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Shi, J. et al. PD-1 controls follicular T helper cell positioning and function. Immunity 49, 264–274.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Ekman, I. et al. Circulating CXCR5PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes. Diabetologia 62, 1681–1688 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Bocharnikov, A. V. et al. PD-1hiCXCR5 T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI Insight 4, e130062 (2019).

    PubMed Central  Article  PubMed  Google Scholar 

  40. 40.

    Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Fortea-Gordo, P. et al. Two populations of circulating PD-1hiCD4 T cells with distinct B cell helping capacity are elevated in early rheumatoid arthritis. Rheumatology (Oxford) 58, 1662–1673 (2019).

    Article  Google Scholar 

  42. 42.

    Bell, E. B. et al. Both CD45Rlow and CD45Rhigh “revertant” CD4 memory T cells provide help for memory B cells. Eur. J. Immunol. 31, 1685–1695 (2001).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Merica, R., Khoruts, A., Pape, K. A., Reinhardt, R. L. & Jenkins, M. K. Antigen-experienced CD4 T cells display a reduced capacity for clonal expansion in vivo that is imposed by factors present in the immune host. J. Immunol. 164, 4551–4557 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    McAdam, A. J. et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165, 5035–5040 (2000).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Glinos, D. A., Soskic, B., Jostins, L., Sansom, D. M. & Trynka, G. Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation. Preprint at bioXriv https://www.biorxiv.org/content/10.1101/421099v1 (2018).

  47. 47.

    Weber, J. P. et al. ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. J. Exp. Med. 212, 217–233 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Cabrera, S. M. et al. Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes. Diabetologia 61, 2356–2370 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Linsley, P. S., Greenbaum, C. J., Speake, C., Long, S. A. & Dufort, M. J. B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes. JCI insight 4, e126136 (2019).

    PubMed Central  Article  PubMed  Google Scholar 

  50. 50.

    Monaco, G. et al. flowAI: automatic and interactive anomaly discerning tools for flow cytometry data. Bioinformatics 32, 2473–2480 (2016).

    CAS  PubMed  Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

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.

Corresponding author

Correspondence to Lucy S. K. Walker.

Ethics declarations

Competing interests

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.

Additional information

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.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–8.

Reporting Summary

Supplementary Table 1

Appendix containing patient and experiment data.

Source data

Source Data Fig. 1

Statistical source data

Source Data Fig. 2

Statistical source data

Source Data Fig. 3

Statistical source data

Source Data Fig. 4

Statistical source data

Source Data Fig. 5

Statistical source data

Source Data Fig. 6

Statistical source data

Source Data Fig. 7

Statistical source data

Source Data Fig. 8

Statistical source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing