Activation of bone marrow adaptive immunity in type 2 diabetes: rescue by co-stimulation modulator Abatacept
Anita C. Thomas,
Posted 04 Jul 2020
bioRxiv DOI: 10.1101/2020.07.03.187088
Posted 04 Jul 2020
Hypothesis: Type 2 diabetes (T2D) is characterized by low-grade inflammation. Here, we investigated the state of adaptive immunity in bone marrow (BM) of patients and mice with T2D. We also tested if inhibition T cell co-stimulation by Abatacept could rescue the immune profile of T2D mice. Methods: Flow-cytometry and cytokine analyses were performed on BM samples from patients with or without T2D. Moreover, we studied the immune profile of db/db and control wt/db mice. A cohort of db/db mice was randomized to receive Abatacept or vehicle for 4 weeks, with endpoints being immune cell profile and indexes of insulin sensitivity and heart performance. Results: T2D patients showed increased frequencies of BM CD4+ (2.8-fold, p=0.001) and CD8+ T cells (1.8-fold, p=0.01), with upregulation of the activation marker CD69 and homing receptor CCR7 in CD4+ (1.64-fold, p=0.003 and 2.27-fold, p=0.01, respectively) and CD8+ fractions (1.79-fold, p=0.05 and 1.69-fold, p=0.02, respectively). CCL19 (CCR7 receptor ligand) and CXCL10/11 (CXCR3 receptor ligands), implicated in T cell migration and activation, were the most differentially modulated chemokines. Studies in mice confirmed the activation of adaptive immunity in T2D. Abatacept reduced the activation of T cells and levels of pro-inflammatory chemokines and cytokines. Additionally, Abatacept improved indexes of cardiac systolic function, but not insulin sensitivity. Conclusions: These novel findings support the concept of BM adaptive immune activation in T2D. Modulation of T cell co-stimulation could represent an attractive and immediately available modality to dampen inappropriate activation of adaptive immune response and protect from target organ damage. ### Competing Interest Statement The authors have declared no competing interest.
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