bioRxiv. 2026 Jul 03. pii: 2026.06.27.734105. [Epub ahead of print]
Shiva Pathak,
Rizwan Ahmed,
Nadine Nagy,
Sooyeon Lee,
Cameron S Bader,
Shobha Regmi,
Bettina P Iliopoulou,
Pin-I Chen,
Biki Gupta,
Alejandro Villar-Prados,
Yong Bin Kim,
Noor Hussein,
Emily SooHoo,
Abigail Twoy,
Avnesh S Thakor,
Kent P Jensen,
Paul J Utz,
Mark M Davis,
Justin P Annes,
Everett H Meyer.
Type 1 diabetes (T1D) is caused by T cell-mediated autoimmune destruction of insulin-producing islet β-cells. Treatment with T-cell depleting therapies delays the progression of stage 2 and 3 T1D, but these agents exert broad immunosuppressive effects on T cell populations, including T regulatory cells (Tregs), which are key in promoting immune tolerance. We evaluated non-obese diabetic (NOD) mice and recently diagnosed T1D patients and identified CD38 as a marker for pathogenic T cell populations. Using adoptive T-cell transfer in Recombination Activating Gene 1 knockout NOD mice and in a humanized mouse model of autoimmune diabetes, we demonstrated that CD38-expressing autoreactive T cells drive diabetes pathogenesis. Furthermore, we found that selective depletion of CD38 + cells, using an anti-CD38 monoclonal antibody (mAb), prevents insulitis and diabetes onset without depleting CD4 + CD25 + Tregs. Administration of anti-CD38 mAb did not adversely affect islet function and may selectively eliminate immunogenic senescent islet β-cells. These results support the strategy of selectively depleting diabetogenic T cells using an anti-CD38 mAb to treat T1D and restore immune tolerance. Therefore, transient depletion of autoreactive T cells using anti-CD38 mAb may provide a novel strategy to prevent or abrogate β-cell autoimmunity in T1D.
One sentence summary: Pathogenic autoreactive are characterized by CD38 overexpression, and their selective depletion with anti-CD38 monoclonal antibody prevents autoimmune diabetes.