Scientific Oral Abstracts (Basic)

DC2420 - Cytotoxic T Cell Injury Drives Beta Cell Senescence Entry in Type 1 Diabetes

Friday, November 22, 2024

10:00 - 11:15 AT Time

Location: Room 201

Presenter(s)

Jasmine Pipella, BSc (she/her/hers)

PhD Student
University of Manitoba
Winnipeg, Manitoba, Canada

Disclosure(s): I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose

Blinded Abstract:

Background:
In 2022, the FDA approved the anti-CD3 immunotherapy Teplizumab to delay symptomatic Type 1 Diabetes (T1D), although the mechanism involved remains unclear. Evidence shows some β-cells escape death and instead undergo senescence during T1D. This study aimed to determine whether anti-CD3, which mitigates β-cell destruction by cytotoxic T cells, also impacts senescent β-cell accumulation during T1D.

METHODS/

Results:
Female NOD/ShiLtJ mice received four weekly doses of anti-CD3 or IgG at the presymptomatic stage to mimic Teplizumab and their pancreas/pancreatic islets and spleen were analyzed to examine disease progression and β-cell senescence. Anti-CD3 mice exhibited decreases in CD3+ T cells (p < 0.0005), fewer insulin-specific T cells (p < 0.05) and fewer total CD4+ T cells (p < 0.0001), without an effect on regulatory T cells (p=0.80). Anti-CD3 mice also displayed improved glucose tolerance (p < 0.05), more β-cells (p < 0.05) and reduced insulitis (p < 0.05), as expected. Strikingly, examination of markers of senescence revealed that anti-CD3 treatment decreased senescence gene expression (p < 0.05) and decreased the frequency of senescent β-cells (p < 0.0005), without affecting other pathways. Combining anti-CD3 with ABT-199, a senolytic known to halt T1D progression in NOD mice, provided additional benefit, further improving glucose tolerance (p < 0.05), decreasing senescent β cells (p < 0.005), and reducing insulitis (p < 0.005) compared to controls.

Conclusions:
Our results demonstrate that anti-CD3 at the pre-symptomatic stage of T1D has a novel effect of limiting senescent β cell accumulation. We propose that cytotoxic T cell injury triggers senescence entry in a subset of β-cells during T1D.