Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes
Laura M. Jacobsen, … , Peter S. Linsley, Todd M. Brusko
Laura M. Jacobsen, … , Peter S. Linsley, Todd M. Brusko
Published July 11, 2023
Citation Information: JCI Insight. 2023;8(16):e161812. https://doi.org/10.1172/jci.insight.161812.
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Clinical Research and Public Health Endocrinology Immunology

Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes

Abstract

BACKGROUND Low-dose anti–thymocyte globulin (ATG) transiently preserves C-peptide and lowers HbA1c in individuals with recent-onset type 1 diabetes (T1D); however, the mechanisms of action and features of the response remain unclear. Here, we characterized the post hoc immunological outcomes of ATG administration and their potential use as biomarkers of metabolic response to therapy (i.e., improved preservation of endogenous insulin production).METHODS We assessed gene and protein expression, targeted gene methylation, and cytokine concentrations in peripheral blood following treatment with ATG (n = 29), ATG plus granulocyte colony–stimulating factor (ATG/G-CSF, n = 28), or placebo (n = 31).RESULTS Treatment with low-dose ATG preserved regulatory T cells (Tregs), as measured by stable methylation of FOXP3 Treg-specific demethylation region (TSDR) and increased proportions of CD4+FOXP3+ Tregs (P < 0.001) identified by flow cytometry. While treatment effects were consistent across participants, not all maintained C-peptide. Responders exhibited a transient rise in IL-6, IP-10, and TNF-α (P < 0.05 for all) 2 weeks after treatment and a durable CD4+ exhaustion phenotype (increased PD-1+KLRG1+CD57– on CD4+ T cells [P = 0.011] and PD1+CD4+ Temra MFI [P < 0.001] at 12 weeks, following ATG and ATG/G-CSF, respectively). ATG nonresponders displayed higher proportions of senescent T cells (at baseline and after treatment) and increased methylation of EOMES (i.e., less expression of this exhaustion marker).CONCLUSION Altogether in these exploratory analyses, Th1 inflammation-associated serum and CD4+ exhaustion transcript and cellular phenotyping profiles may be useful for identifying signatures of clinical response to ATG in T1D.TRIAL REGISTRATION ClinicalTrials.gov NCT02215200.FUNDING The Leona M. and Harry B. Helmsley Charitable Trust (2019PG-T1D011), the NIH (R01 DK106191 Supplement, K08 DK128628), NIH TrialNet (U01 DK085461), and the NIH NIAID (P01 AI042288).

Authors

Laura M. Jacobsen, Kirsten Diggins, Lori Blanchfield, James McNichols, Daniel J. Perry, Jason Brant, Xiaoru Dong, Rhonda Bacher, Vivian H. Gersuk, Desmond A. Schatz, Mark A. Atkinson, Clayton E. Mathews, Michael J. Haller, S. Alice Long, Peter S. Linsley, Todd M. Brusko

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Figure 1

C-peptide AUC change over time for responders and nonresponders.

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C-peptide AUC change over time for responders and nonresponders. The mea...
The mean C-peptide AUC values for each treatment arm (ATG, blue; ATG/G-CSF, green; placebo, red) were disaggregated by responders (solid line) or nonresponders (dashed line). Response is based on the definition of an individual participant slope from baseline to 48 weeks being above the median (responders) or below the median (nonresponders) for the entire cohort, with the number of participants listed above or below the graph, respectively. The model included participant-level random effects terms for the intercept and slopes (16). The remaining clinical trial C-peptide AUC data from 48 weeks to 96 weeks are shaded in gray, as they were not part of the response definition. There were 582 samples collected, including 196 in the placebo group, 197 in the ATG group, and 189 in the ATG/G-CSF group. Among these, 279 samples were from the nonresponder group and 303 samples were from the responder group.