Neuroendocrine hormones of the hypothalamus-pituitary-thyroid axis can exert positive or negative immunoregulatory effects on intestinal lymphocytes, Small intestine epithelial cells were found to express receptors for thyrotropin-releasing hormone (TRH) and to be a primary source of intestine-derived thyroid-stimulating hormone (TSH). The gene for the TSH receptor (TSH-R) was expressed in intestinal T cells but not in epithelial cells, which suggested a hormone-mediated link between lymphoid and nonhematopoietic components of the intestine, Because mice with congenitally mutant TSH-R (hyt/hyt mice) have a selectively impaired intestinal T cell repertoire, TSH may be a key immunoregulatory mediator in the intestine.