Circulating CXCR5-PD1hi peripheral T helper cells are increased in children with T1D and in autoantibody-positive children at-risk for T1D

Background: Type 1 diabetes (T1D) is almost invariably preceded by positivity for islet autoantibodies. Recent studies have shown that circulating T follicular helper (Tfh) cells are increased in patients with T1D. Together, these findings support an important role for T-B-cell interactions in T1D pathogenesis. A new subset of T cells, peripheral helper T cell (Tph) capable of promoting B cell responses and antibody production in inflamed tissues has recently been observed to be associated with rheumatoid arthritis. It is unclear, however, whether Tph cells play a role in the development of T1D. 

Methods: We used multicolor flow cytometry and cell sorting to characterize peripheral blood CXCR5-PD1hi memory CD4+ T cells. The frequency of CXCR5-PD1hi T cells was analyzed in a clinical cohort of 48 children with newly diagnosed T1D, 40 autoantibody-positive at-risk children and 86 age-matched autoantibody-negative control children. 

Results: We confirmed that CXCR5-PD1hi Tph cells share several features with CXCR5+PD1hi Tfh cells, such as the high expression of ICOS and IL-21 but also displayed higher expression of chemokine receptors associated with trafficking to inflamed tissues, such as CCR2, CX3CR1 and CCR5, than Tfh cells. Tph cells were also able to activate memory B cells into antibody-secreting plasma cells as efficiently as Tfh cells. We observed that the frequency of peripheral blood Tph cells was increased both in children with newly-diagnosed T1D and in autoantibody-positive children at-risk for the disease when compared to healthy children. Additional flow-cytometric analyses revealed that the expanded population of CXCR5-PD1hi Tph cells in individuals with T1D-associated autoimmunity also expresses the marker TIGIT.

Conclusion: Our results demonstrate that a novel population of circulating CXCR5-PD1hi Tph cells with B-cell activating potential is expanded in individuals with T1D-associated autoimmunity. Consequently, Tph cells could have potential both as a biomarker of T1D progression and as a target for immunotherapy.