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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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 7

Intrathymic IL-4 has a differential influence on the diversity of the TCRV-β repertoire at the onset of T1D.

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Intrathymic IL-4 has a differential influence on the diversity of the TC...
4-week-old NOD mice (4 per group) were treated i.t. with IL-4 or PBS (NIL) once per week for 2 weeks. At the onset of diabetes (12 weeks of age), the SP and PLN were harvested, the cells were pooled and used to sort TCR-β+ T cells. RNA isolated from these T cells was utilized to generate cDNA libraries, and the variable region of the TCR-β chain was sequenced by iRepertoire Inc. A shows 2D heat maps of the relative frequency of V (y-axis) and J (x-axis) segments of TCR-β chain. V-J heat maps from the SP (top panels) and PLN (bottom panels) are illustrated. B shows the percentage of V-β13 usage (bold segments) in IL-4 (outer donut chart) versus NIL-treated (inner donut chart) mice from SP and PLN T cells. C shows the percentage of different V-β reads that have undergone a range of nucleotide trimming in comparison to their parental germline genes. D shows the percentage of T cells with CDR3s encompassing different assortments of N additions. E shows the percentage of short (27–36 nt) and long (37–45 nt) CDR3 reads among IL-4 and NIL-treated mice. Positively selected thymocytes (CD45.1+ CD4+ CD8+ CD69+) were sorted from 6–8wk old NOD.BDC2.5 thymi and injected i.t. into congenic (CD45.2+) NOD recipients. The left panel depicts the CD45.1 donor BDC2.5 cells and the right panel shows the percent of cells incorporating the fixable viability dye (FVD+) relative to FVD– cells in each the 5 recipients. **P < 0.01 as determined by 2-tailed, unpaired Student’s t test.