Double positive (DP) developing thymocytes regulate the development of neuronal cell bodies within the thymus 2260542

Abstract

Abstract Introduction Peripheral nervous system innervation of various organs has been associated with the development and maintenance of the immune system. Yet, the intricate details of thymic innervation remain less well-studied. Interestingly, various neurological insults including brain tumors, and neurotropic infections have been shown to have profound impacts on thymic size and cellularity and T cell development. Methods We used flow cytometry, confocal microscopy, neuro tracers, and genetic knockout mice to evaluate developing T cell-neuron interactions within the thymus. Results We have identified neuronal cell bodies within the thymus. These cells express neuronal markers such as NeuN and tyrosine hydroxylase and lack TEC identifiers, such as EpCAM, UEA-1, and Ly51. Thymic neurons can be infected with a neurotropic rabies vector, further cementing their neuronal identity. Considering the thymus consists mostly of T cells, we next investigated a potential interaction between T cells and thymic neurons. Interestingly, loss of T cell development results in a lack of thymic neuron development indicating T cell-neuron coregulation during development. However, thymic neurons can be recovered following a bone marrow transplant, suggesting the provision of a differentiation and/or survival signal for neurons provided by the developing T cells. Using knockout mice lacking the T cell lineage at various stages of development, we determined that TCR beta selection is required for the development of thymic neurons. Finally, we determined that a lack of transition from DN4 to DP severely diminishes the development of thymic neurons. Analysis of the publicly available bulk RNA-sequencing data comparing thymic DP to DN cell populations indicates the potential involvement of IL34 in neuronal development in the thymus. Conclusion We describe a novel population of neuronal cells within the thymus that interact with developing thymocytes to establish optimal thymic architecture. Funding Source NIH K99/R00 Topic Categories Neuroimmunology (NEUR)