T-cell - Restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Abstract

Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bettg/wtand T-bettg/tg) toinvestigate theeffectsofT-betoverexpressionselectivelyin T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, aswell as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bettg/wtand T-bettg/tgmice, respectively. T-bettg/tgalveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impairedfunction, in additionto augmented T-cell infiltration. In addition, PAP development in T-bettg/tgmice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide newinsight into themolecular pathogenesis of secondary PAP accompanied by hematologic disorders.