Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression

Abstract

Multiple studies of B-and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T-and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.

The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

“…This underlies the complexity of the disease in that different DR heterodimers may elicit both CD4 + T effectors as well as Tregs. It is the overall immune response, together with other T1D susceptibility genes and unknown environmental conditions, that determines β-cell autoimmune response eventually evolving to clinical type 1 diabetes [ 48 , 49 ]. The convenient separation of naïve, effector and regulatory CD4 + T cells into various subpopulations by cytometry may demonstrate the relative distribution of epitope-specific T cells into the various subpopulations, with distinct pathogenic properties and roles [ 50 , 51 ].…”

Uncovering Pathways to Personalized Therapies in Type 1 Diabetes

“…T-cell autoreactivity is a major component of the immune response in T1D, with activated cells expressing markers of immune memory and self-renewal as hallmarks of disease (30)(31)(32)(33). Various drugs that deplete T cells or interfere with T-cell function have been tested in T1D clinical trials, and analysis of T-cell subsets reveals that differences in treatment efficacy are correlated with differential effects on different T-cell subsets.…”

Identifying the ‘Achilles heel’ of type 1 diabetes

“…Furthermore, studies of human cohorts at risk for developing T1D also implicate B cells in disease initiation, with the presence of two or more autoantibodies targeting islets as a hallmark of early-stage T1D prior to clinical diagnosis [17]. There is also emerging evidence that B cell homeostasis and function is impaired in 'at-risk' cohorts [11,18,19]. Reported alterations include increased frequency of transitional B cells, reduced frequency of anergic B cells and dynamic alterations in both B cell receptor and IL-21 responses.…”