| First Author | Borelli A | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 6976 |
| PubMed ID | 39143070 | Mgi Jnum | J:353966 |
| Mgi Id | MGI:7713808 | Doi | 10.1038/s41467-024-51164-5 |
| Citation | Borelli A, et al. (2024) Lymphotoxin limits Foxp3(+) regulatory T cell development from Foxp3(lo) precursors via IL-4 signaling. Nat Commun 15(1):6976 |
| abstractText | Regulatory T cells (T(reg)) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25(+)Foxp3(-) and CD25(-)Foxp3(lo) precursors. However, the mechanisms regulating the recently identified Foxp3(lo) precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) heterocomplex is upregulated during T(reg) development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of T(reg) from Foxp3(lo) precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTalpha(1)beta(2)-lymphotoxin beta receptor-mediated interactions with mTEC limit T(reg) development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic T(reg) development that fine-tunes the Foxp3(lo) T(reg) precursor pathway by limiting IL-4 availability. |
