Neurotransmitters Modulate Intrathymic T-cell Development

Abstract

The existence of a crosstalk between the nervous and immune systems is well established. Neurotransmitters can be produced by immune cells, whereas cytokines can be secreted by cells of nervous tissues. Additionally, cells of both systems express the corresponding receptors. Herein, we discuss the thymus as a paradigm for studies on the neuroimmune network. The thymus is a primary lymphoid organ responsible for the maturation of T lymphocytes. Intrathymic T-cell development is mostly controlled by the thymic microenvironment, formed by thymic epithelial cells (TEC), dendritic cells, macrophages, and fibroblasts. Developing thymocytes and microenvironmental cells can be influenced by exogenous and endogenous stimuli; neurotransmitters are among the endogenous molecules. Norepinephrine is secreted at nerve endings in the thymus, but are also produced by thymic cells, being involved in controlling thymocyte death. Thymocytes and TEC express acetylcholine receptors, but the cognate neurotransmitter seems to be produced and released by lymphoid and microenvironmental cells, not by nerve endings. Evidence indicates that, among others, TECs also produce serotonin and dopamine, as well as somatostatin, substance P, vasoactive intestinal peptide (VIP) and the typical pituitary neurohormones, oxytocin and arg-vasopressin. Although functional data of these molecules in the thymus are scarce, they are likely involved in intrathymic T cell development, as exemplified by somatostatin, which inhibits thymocyte proliferation, differentiation, migration and cytokine production. Overall, intrathymic neuroimmune interactions include various neurotransmitters, most of them of non-neuronal origin, and that should be placed as further physiological players in the general process of T-cell development.

Bidirectional crosstalk between the peripheral nervous system and lymphoid tissues/organs

“…It modulates the expression of adhesion molecules (e.g., Thy-1 (CD90)) on thymic epithelial cells (TECs), which facilitate the interaction and movement of developing T cells ( 49 ). This intricate interplay between sympathetic fibers and thymic cells helps to orchestrate the maturation processes and the formation of a diverse and functional T-cell repertoire ( 50 ). For example, chronic stress-induced loss of sympathetic innervation can affect thymic development and T cell development/maturation ( 51 ).…”

“…Several neuropeptides (e.g., neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP)) have been shown to contribute to the regulation/modulation of immune processes (e.g., T cell development and maturation) inside the thymus ( 41 , 50 ). For example, SP and CGRP play essential roles in the differentiation, proliferation, and maturation of thymocytes.…”

“…The immune cells within the thymus express various receptors for neurotransmitters/neuropeptides, allowing them to sense and respond to neuronal signals. For example, thymocytes possess β2-AR, cholinergic receptors, and other neurotransmitter/neuropeptide receptors that can influence thymocyte activation, proliferation, and migration inside the thymus ( 49 , 50 ).…”

Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

“…Intrathymic thymocyte differentiation and migration, from the entrance of precursor cells to the exit of mature SP cells, is dependent on interactions controlled by the thymic tridimensional network. This is composed by cellular components such as thymic epithelial cells (TEC), thymic dendritic cells (TDC), macrophages and fibroblasts, as well as non-soluble and soluble molecules such as the extracellular matrix (ECM) proteins fibronectin, laminin, type I and IV collagens; cytokines as interleukin (IL)-2, IL-6, IL-7, and IL-22; chemokines as CXCL12, CCL4, and CCL7; hormones as thymosin, thymopoietin, and thymulin; and different typical soluble components of nervous tissues, such as neuropeptides and neurotransmitters ( 12 , 15 , 16 ).…”

The Single-Cell Transcriptomic Analysis of Prefrontal Pyramidal Cells and Interneurons Reveals the Neuronal Expression of Genes Encoding Antimicrobial Peptides and Immune Proteins

“…However, the communication from neurons to adaptive immune cells is less established. Immune cells express the receptors of neurotransmitters (12) and a direct regulatory action of neurotransmitters on T cell maturation is demonstrated (13). T and B cells can enter the CNS under both physiological and pathological conditions (14)(15)(16) and some of them can come into close contact with neurons (17,18).…”