Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review)

Abstract

The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics.

Figure 1.

T cell development in the thymus. CD, cluster of differentiation; CMJ, corticomedullary junction; cTEC, cortical thymic epithelial cell; DN, differentiation; DP, double positive; mTEC, medullary thymic epithelial cell; SP, single positive.

Figure 2.

Molecular mechanisms underlying the generation of thymic regulatory T cells. Molecular signals downstream of the TCR are presented. AP, activator protein; APC, antigen-presenting cell; BCL, B cell lymphoma; BTLA, B and T lymphocyte attenuator; Ca, calcium; CARMA, CARD-containing MAGUK protein; CD, cluster of differentiation; DAG, diacylglycerol; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; IKKβ, inhibitor of nuclear factor κB; ITIM, immunoreceptor tyrosine-based inhibition motif; MEK, mitogen-activated extracellular signal-regulated kinase; MHC, major histocompatibility complex; FoxO, forkhead box protein O; FOXP3, forkhead box protein 3; NFAT, nuclear factor of activated T; Grb, growth factor receptor-bound protein; LAT, linker for activation of T cells; LCK, lymphocyte-specific protein tyrosine kinase p56; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein; mTOR, mechanistic target of rapamycin; NF, nuclear factor; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PK, protein kinase; PL, phospholipase; PTP, protein-tyrosine phosphatase; Ras, rat sarcoma also known as p21; Raf, rapidly accelerated fibrosarcoma; SHP, SH2-containing protein tyrosine phosphatase; SOS, Son of Sevenless; STIM, stromal interaction molecule; TAK, transforming growth factor beta-activated kinase; ZAP70, ζ-associated protein of 70 kD.

Figure 3.

Role of cytokines in T cell development. CD, cluster of differentiation; DN, double negative; DP, double positive; IL, interleukin; Treg, regulatory T cell.

Figure 4.

Model of stress-induced thymic atrophy, and thymosuppressive and thymostimulatory mediators. AIDS, acquired immunodeficiency syndrome; Cyc, cyclophosphamide; Dex, dexamethasone; Dox, doxorubicin; HIV, human immunodeficiency virus; hGH, human growth hormone; IL, interleukin; KGF, keratinocyte growth factor; TGF-β, transforming growth factor-β; TSLP, thymic stromal lymphopoietin.