Dynamic regulation of intestinal immunity by hormones of the hypothalamus-pituitary-thyroid axis

The role of the thymus in the development of murine small intestinal intraepithelial lymphocytes (IELs) has been a controversial topic for decades. This controversy has been further propagated by observations that differences in IEL repertoires vary according to the particular athymic animal model system used to study IELs. In an attempt to understand the bases for these differences, we have undertaken a series of experiments designed to explore the extent to which extraimmunologic events, in particular neuroendocrine factors, play a role in the development of extrathymic IELs. As discussed here, these studies indicate that hormones of the hypothalamus-pituitary-thyroid (HPT) axis exert either positive or negative regulatory effects on intestinal IELs, depending upon the particular hormone. Although the mechanisms by which HPT hormones influence IEL development and immune regulation have yet to be fully delineated, it appears that thyroid-stimulating hormone is a key mediator in this process, and that this may occur via local autocrine/paracrine responses within the intestine itself. The implications of these findings in the context of immunity and disease at the level of the gastrointestinal tract are discussed.