Circulating CXCR5(−)PD-1(hi) peripheral T helper cells are associated with progression to type 1 diabetes

AIMS/HYPOTHESIS: Type 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5(−)PD-1(hi)) peripheral T helper (Tph) cells, in human type 1 diabetes. METHODS: The phenotype of blood CXCR5(−)PD-1(hi) CD4(+) T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5(−)PD-1(hi) T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb(+)) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children. RESULTS: Circulating CXCR5(−)PD-1(hi) Tph cells share several features associated with B cell helper function with circulating CXCR5(+)PD-1(hi) follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our results demonstrate that circulating CXCR5(−)PD-1(hi) Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-019-4936-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.