Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice
Alexis N. Cattin-Roy, … , Adam G. Schrum, Habib Zaghouani
Alexis N. Cattin-Roy, … , Adam G. Schrum, Habib Zaghouani
Published December 2, 2024
Citation Information: J Clin Invest. 2024;134(23):e163417. https://doi.org/10.1172/JCI163417.
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Research Article Autoimmunity

Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice

Abstract

Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.

Authors

Alexis N. Cattin-Roy, Kimberly G. Laffey, Luan B. Le, Adam G. Schrum, Habib Zaghouani

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Figure 2

NOD HR+ETPs fate decision is restricted to T cells in vivo.

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NOD HR+ETPs fate decision is restricted to T cells in vivo. CD45.1 NOD H...
CD45.1 NOD HR+ETPs were injected i.t. into CD45.2 NOD, while CD45.2 B6 HR+ETPs were injected i.t. into CD45.1 B6 recipients. After 16 days, thymi were harvested and HR+ETP-derived cells were analyzed for lineage phenotype. A shows representative contour plots for expression of CD11b, CD11c, and CD3 markers. B shows the mean percentage ± SD of CD11c+ DCs (top panel) and CD3+ T cells (bottom panel) from 3 experiments represented by squares for B6 and circles for NOD mice. ***P < 0.001 as determined by 2-tailed, unpaired Student’s t test. (C) Contour plot (left panel) shows a representative experiment for CD4 and CD8 expression on NOD HR+ETP-derived T cells. The right panel shows the mean percentage ± SD of CD4 and CD8 expression from 3 experiments for each strain. D illustrates a representative experiment analyzing expression of other lymphoid lineage phenotypes including Tet+ iNKT cells (left panel) and CD19+ B cells (right panel). (E) Frequency of cDC1 and cDC2 subsets relative to total CD11c+ MHC II+ thymic DCs in NOD (circles), B6 (squares), and B6.NOD (triangle) mice. Each symbol represents 1 mouse for a total of 6–8 mice per group. *P < 0.001 as determined by 1-way ANOVA with Tukey’s post hoc test.