Neural control of regulatory T-cell generation in thymus

Regulatory T cells, like other conventional T cells mature in discrete stromal regions in the thymus innervated by adrenergic fibers of the sympathetic nervous system (SNS). While the SNS is known to influence various physiological processes, its role in the control of thymic hematopoiesis through the interaction with higher regulatory centers, such as the hypothalamus remained unexplored. Here we demonstrate that hypothalamic Agouti-related protein (AgRP) neurons modulate the maturation of regulatory T cell through SNS by inhibiting β-3 adrenergic receptors (B3AR) expressed by target thymic stromal cells. Indeed, chemogenetic activation of these neurons reduced NE in the thymus, attenuating B3AR activity, increasing IL-15 expression, and promoting the expansion of regulatory T cells. In experimental autoimmune encephalomyelitis (EAE), a T cell mediated mouse model of multiple sclerosis (MS) increased noradrenergic signaling alters the composition of thymic T cells, particularly in the cortical region where first stages of T cell maturation occur. Importantly, pharmacological inhibition of B3ARs delayed EAE onset, reduced disease severity, and increased thymic Treg frequency. These findings highlight the importance of SNS-B3AR axis as regulator of thymic stromal cell function and Treg production during autoimmune inflammation. Our study unveils a novel mechanism involving AgRP neurons in the regulation of the immune system mediated by noradrenergic transmission, with potential clinical relevance for immune-mediated diseases.