Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling
Alexia Borelli, Jérémy C. Santamaria, Cloé Zamit, Cécile Apert, Jessica Chevallier, Philippe Pierre, Rafael J. Argüello, Lionel Spinelli, Magali Irla
Abstract
Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3− and CD25−Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1β2 (LTα1β2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo 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 LTα1β2-lymphotoxin β receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability. Regulatory T cells (Treg) develop in the thymus via two pathways including CD25−Foxp3lo and CD25+Foxp3− cells. Here, the authors show that lymphotoxin acts as an inhibitory checkpoint of thymic Treg development, fine-tuning the Foxp3lo precursor pathway by limiting IL-4 production in medullary thymic epithelial cells.