Lymphotoxin Limits Foxp3 Regulatory T Cell Development from Foxp3 Precursors Via IL-4 Signaling

Regulatory T cells (T) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25Foxp3 and CD25Foxp3 precursors. However, the mechanisms regulating the recently identified Foxp3 precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin αβ (LTαβ) heterocomplex is upregulated during T development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of T from Foxp3 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 LTαβ-lymphotoxin β receptor-mediated interactions with mTEC limit T development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic T development that fine-tunes the Foxp3 T precursor pathway by limiting IL-4 availability.