Thyroid Hormone Receptor α1 Mutants Impair B Lymphocyte Development in a Mouse Model.

Mutations of the thyroid hormone receptor α () gene cause resistance to thyroid hormone (RTHα). RTHα patients exhibit very mild abnormal thyroid function test results (serum triiodothyronine can be high-normal to high; thyroxine normal to low; thyrotropin is normal or mildly raised) but manifest hypothyroid symptoms with growth retardation, delayed bone development, and anemia. Much has been learned about the molecular actions in TRα1 mutants affecting abnormal growth, bone development, and anemia by using a mouse model of RTHα ( mice). However, it is not clear whether TRα1 mutants affect lymphopoiesis in RTHα patients. The present study addressed the question of whether TRα1 mutants could cause defective lymphopoiesis. We assessed lymphocyte abundance in the peripheral circulation and in the lymphoid organs of mice. We evaluated the effect of thyroid hormone on B cell development in the bone and spleen of these mice. We identified key transcription factors that are directly regulated by TRα1 in the regulation of B cell development. Compared with wild-type mice, a significant reduction in B cells, but not in T cells, was detected in the peripheral circulation, bone marrow, and spleen of mice. The expression of key transcription regulators of B cell development, such as , , and 5, was significantly decreased in the bone marrow and spleen of mice. We further elucidated that the gene, essential for lineage specification in the early B cell development, was directly regulated by TRα1. Thus, mutations of TRα1 could impair B cell development in the bone marrow via suppression of key regulators of B lymphopoiesis. Analysis of lymphopoiesis in a mouse model of RTHα showed that B cell lymphopoiesis was suppressed by TRα1 mutations. The suppressed development of B cells was, at least in part, via inhibition of the expression of key regulators, , , and 5, by TRα1 mutations. These findings suggest that the mutations of the gene in patients could lead to B cell deficiency.