3024-LB: T Stem Cell Memory Levels in Relation to Progression and Treatment Response across Stages of Type 1 Diabetes

Introduction and Objective: T cells play a primary role in the autoimmune-driven loss of insulin-producing beta cells in Type 1 diabetes (T1D). Levels of T stem cell memory (TSCM) cells, which can continually give rise to effector T cells, are elevated in T1D subjects, including in disease-relevant antigen-specific cells. We hypothesized that TSCM may indicate or contribute to active disease, and tested if circulating TSCM levels were associated with natural progression or response to immunotherapy in subjects with T1D stages 1, 2, and 3. Methods: Cytometry data from multiple TrialNet (KQ1, TN18, TN19) and ITN (EXTEND) studies in at-risk individuals and new onset T1D were re-analyzed to gate for CD4 and CD8 TSCM cells at baseline and later time points. We used linear and generalized additive models to test for associations between baseline TSCM frequencies or changes in TSCM levels and disease progression or treatment response, as measured by transitions from stage 1/2 to 2/3 and metabolic outcomes including C-peptide quantitative response (QR) in stage 3 disease. Models included age, sex, BMI, and number of T1D autoantibodies as covariates. Results: TSCM levels were stable within individuals across several years in the absence of immune-modifying treatments but were strongly perturbed by some immunotherapies. Baseline CD8 TSCM levels were marginally associated with C-peptide loss in placebo-treated stage 3 T1D in an age-dependent manner, but this was not supported in an independent validation dataset. We did not find evidence of CD4 or CD8 TSCM levels associating with treatment response, or with progression in other stages of T1D. TSCM levels did correlate with age and BMI, but their inclusion as covariates did not affect associations with disease variation. Conclusion: Circulating TSCM levels do not clearly associate with disease progression or treatment response in T1D stage 1, 2, and 3, suggesting elevated levels of TSCM may not be linked to disease pathogenesis. Disclosure M. Dufort: None. J. Chen: None. A. Long: Advisory Panel; Current; Diamyd. Consultant; Current; Sanofi. Research Support; Ended; Novo Nordisk. Consultant; Current; SAB Biotherapeutics, Inc. C. Speake: Consultant; Ended; GentiBio. Advisory Panel; Ended; Sanofi. Consultant; Current; Cour Pharmaceuticals. Research Support; Ended; Cour Pharmaceuticals. K.S. Cerosaletti: Research Support; Current; Cour Pharmaceuticals, GentiBio, Inc, InduPro Therapeutics. Consultant; Ended; Mozart Therapeutics. Other - Research collaboration supported by Breakthrough T1D grant funding; Ended; Base5 (Benthic) Genomics. Research Support; Ended; IM Therapeutics. Funding American Diabetes Association (11-22-IBSPM-17)