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The CD137 Ligand Is Important for Type 1 Diabetes Development but Dispensable for the Homeostasis of Disease-Suppressive CD137⁺ FOXP3⁺ Regulatory CD4 T Cells.

ABSTRACT: CD137 modulates type 1 diabetes (T1D) progression in NOD mice. We previously showed that CD137 expression in CD4 T cells inhibits T1D, but its expression in CD8 T cells promotes disease development by intrinsically enhancing the accumulation of β-cell-autoreactive CD8 T cells. CD137 is expressed on a subset of FOXP3⁺ regulatory CD4 T cells (Tregs), and CD137⁺ Tregs are the main source of soluble CD137. Soluble CD137 suppresses T cells in vitro by binding to the CD137 ligand (CD137L) upregulated on activated T cells. To further study how the opposing functions of CD137 are regulated, we successfully targeted Tnfsf9 (encoding CD137L) in NOD mice using the CRISPR/Cas9 system (designated NOD.Tnfsf9 ^-/-). Relative to wild-type NOD mice, T1D development in the NOD.Tnfsf9 ^-/- strain was significantly delayed, and mice developed less insulitis and had reduced frequencies of β-cell-autoreactive CD8 T cells. Bone marrow chimera experiments showed that CD137L-deficient hematopoietic cells were able to confer T1D resistance. Adoptive T cell transfer experiments showed that CD137L deficiency on myeloid APCs was associated with T1D suppression. Conversely, lack of CD137L on T cells enhanced their diabetogenic activity. Furthermore, neither CD137 nor CD137L was required for the development and homeostasis of FOXP3⁺ Tregs. However, CD137 was critical for the in vivo T1D-suppressive activity of FOXP3⁺ Tregs, suggesting that the interaction between CD137 and CD137L regulates their function. Collectively, our results provide new insights into the complex roles of CD137-CD137L interaction in T1D.

SUBMITTER: Foda BM

PROVIDER: S-EPMC7296588 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The CD137 Ligand Is Important for Type 1 Diabetes Development but Dispensable for the Homeostasis of Disease-Suppressive CD137+ FOXP3+ Regulatory CD4 T Cells.

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The CD137 Ligand Is Important for Type 1 Diabetes Development but Dispensable for the Homeostasis of Disease-Suppressive CD137⁺ FOXP3⁺ Regulatory CD4 T Cells.