Circulating CXCR5\u2212PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes

Ilse Ekman,Kirsti Näntö-Salonen,Jorma Toppari,Riitta Veijola,Tyyne Viisanen,Deepak A Rao,Emmi-Leena Ihantola,Jorma Ilonen,Tuure Kinnunen,Mikael Knip

doi:10.1007/s00125-019-4936-8

Abstract

Aims/hypothesisType 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-1hi) peripheral T helper (Tph) cells, in human type 1 diabetes.MethodsThe phenotype of blood CXCR5−PD-1hi CD4+ T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5−PD-1hi 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.ResultsCirculating CXCR5−PD-1hi Tph cells share several features associated with B cell helper function with circulating CXCR5+PD-1hi 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/interpretationOur results demonstrate that circulating CXCR5−PD-1hi 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.

Highlights

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by beta cell destruction and dysfunction [1]
Circulating CXCR5−PD-1hi Tph cells express factors associated with B cell helper function and resemble circulating CXCR5+PD-1hi Tfh cells Based on the expression of CXCR5 and programmed cell death protein 1 (PD-1), human peripheral blood memory CD4+ T cells can be subdivided into PD1−, PD-1int and PD-1hi subsets that are either CXCR5− or CXCR5+ (Fig. 1a)
In line with previously published results [12], both the CXCR5−PD-1hi and CXCR5+PD-1hi subsets expressed high levels of inducible T cell costimulator (ICOS), HLA-DR and T cell immunoreceptor with Ig and ITIM domains (TIGIT) (Fig. 1b–d), with higher expression levels of HLA-DR and lower expression of TIGIT observed in CXCR5−PD-1hi compared with CXCR5+PD-1hi (Fig. 1c,d)

Summary

Introduction

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by beta cell destruction and dysfunction [1]. Autoantibodies produced by B cells are currently the best available biomarker for predicting human type 1 diabetes. Individuals positive for at least two islet autoantibodies have around 50% risk of developing type 1 diabetes within the 5 years [2]. Despite the predictive potential of autoantibodies, it remains unclear whether autoreactive B cells have a direct pathological effect in the pathogenesis of type 1 diabetes. Several studies have shown that B cells are abundant in the pancreatic islets of some individuals with type 1 diabetes, especially in those who are diagnosed at a young age and likely have aggressive autoimmunity [3,4,5]. One clinical trial has demonstrated a partial preservation of C-peptide levels after B cell depletion by rituximab [6]

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