Hormone regulation of murine T cells: Potent tissue-specific immunosuppressive effects of thyroxine targeted to gut T cells

Recent studies in athymic mice indicate that the neuroendocrine hormones thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) can significantly influence the development of lymphoid cells associated with intestinal intraepithelial lymphocytes (IEL). In the present study we have examined the effects of those hormones, as well as of thyroxine (T-4), a thyroid-derived hormone regulated by TSH, on IEL development in euthymic mice. As reported here, whereas IEL in euthymic mice were unaffected by TRH and TSH treatment, T-4 administered to adult euthymic mice at 3 or 6 weeks of age caused a dramatic reduction in the numbers of TCR alpha beta, CD8 alpha beta IEL, i.e. the same subsets previously shown to be up-regulated by TRH and TSH in athymic mice. When given to euthymic mice >8 weeks of age, after TCR alpha beta and CD8 alpha beta subsets had reached normal levels, T-4 had minimal effect on IEL, suggesting that the mode of action of T-4 is directed to developing but not mature IEL. That possibility was confirmed in experiments in which T-4 treatment of bone marrow radiation chimeras during an active phase of T cell regeneration temporarily halted all IEL development at a stage characteristic of immature IEL. Most interesting, the immunosuppressive effects of T-4 were selectively targeted to the intestinal immune system since T-4 had no effect on developing thymocytes or on mature peripheral T cells, in either normal euthymic mice or during hematopoietic reconstitution of radiation chimeras. These findings have implications for understanding intestinal immunity and disease, including chronic intestinal inflammation, in ways not previously appreciated.