Perspectives for Improvement of the Thymic Microenvironment through Manipulation of Thymic Epithelial Cells: A Mini-Review

Abstract

Thymic involution during aging is a major reason for the decreased production of naive T cells and reduced immunity. Alterations within the thymic microenvironment, characterized by the loss of function of thymic epithelial cells (TECs) and fibro-adipogenetic transformation, seem to underlie this process, mainly through declining communication between thymic stromal cells and developing thymocytes. Specifically, the signaling mediated by cytokines and hormones secreted by TECs declines during aging. Many therapies based on the manipulation of growth factors and hormones have succeeded in partially recovering the lymphoid compartment and promoting thymic function. However, considering that aging-induced thymic involution is multifactorial, the thymic reestablishment achieved with treatments that target isolated pathways is incomplete and transitory. Here, we discuss the development of three novel approaches for potentially sustained thymic recovery: the induction of sustained forkhead box N1 expression, the activation of endogenous thymic epithelial progenitor cells (TEPCs), and the generation of TEPCs from pluripotent stem cells. Combined approaches targeting both TECs and lymphoid cells will provide a potentially more effective strategy for sustained rejuvenation of the thymus.

Hormonal control of T-cell development in health and disease

“…[31][32][33] The cortico-medullary tissue architecture is progressively lost, which occurs in parallel with a decline in the export of thymocytes. 34 This process affects the peripheral T-cell compartment, with a consequent decrease in immunoresponsiveness as an indivi dual ages. 35 In addition, the epithelial compartment of ageing mice is altered in both cortical and medullary regions, with reduced numbers of TECs (including mTECs expressing AIRE) and consequently reduced expression of PTAs, 36,37 which in theory favours the generation of autoimmune events in ageing individuals.…”

“…Even so, a number of pre-clinical and clinical approaches to rejuvenate the organ have already been developed that result in substantial improvement in thymus function, such as sex steroid ablation and administration of GH and IL-7. 34,38 Thymic hormone-mediated circuits Hormonal control of the thymus includes both endocrine and paracrine/autocrine pathways that act on thymic microenvironment cells and thymocytes via specific hormone receptors. Accordingly, hormones regulate the proliferation and survival of both lymphoid and thymic microenvironment cells, as well as selection of the T-cell repertoire, which is a mechanism partly related to the modulation of TCR activation upon MHC-peptide binding.…”

“…34,132 Although the overall numbers of T cells are not diminished in the periphery of individuals as they age, naive T cells are replaced by memory T cells in both humans and mice. 133 Furthermore, the ageing process results in suppression of T-cell proliferation, cytokine production and CD8-mediated cytotoxicity, which contributes to a reduced response of T cells.…”

Thymus Regeneration and Future Challenges

“…In this multicellular structure with different cell types and functions several minor stem cell populations can be found, in particular thymic epithelial progenitor cells/thymic epithelial stem cells (TEPC/TESC) [15, 16•], mesenchymal stem cells (MSC) [17,18] and lymphoid progenitor cells (LPC) [12,[19][20][21][22][23][24]. Of these, thymic epithelial cells (TEC) provide most of the specialist functions of the organ [25,26]. As the thymus is organized into two regions, the cortex and the medulla, also TEC are defined according to their localization as cortical (c) and medullar (m) TEC.…”

Transcription‐Related Dynamics from Immune Disability into Endogenous Innovation

“…Early thymus shares the same rudiment with parathyroid for development, [4] with original roles in enhancing reproductive system and adolescence growth, which gives obvious evidence as an erstwhile endocrine organ. [12,13] Yet, owing to inharmonic involution of thymic bioactivity and architecture, peripheral T-cell repertoire development could not match with EMT-CSC constant evolution, resulting in significant increase in clinical cancer incidence and keeping CSC/ EMT pool-targeted strategy an intractable dilemma. Thymic untimely involution may represent a disharmony for a still-evolving erst endocrine organ to the biological burden of lymphopoietic activity.…”