Thymus Gland: A Double Edge Sword for Coronaviruses

Abstract

The thymus is the main lymphoid organ that regulates the immune and endocrine systems by controlling thymic cell proliferation and differentiation. The gland is a primary lymphoid organ responsible for generating mature T cells into CD4+ or CD8+ single-positive (SP) T cells, contributing to cellular immunity. Regarding humoral immunity, the thymic plasma cells almost exclusively secrete IgG1 and IgG3, the two main complement-fixing effector IgG subclasses. Deformity in the thymus can lead to inflammatory diseases. Hassall's corpuscles' epithelial lining produces thymic stromal lymphopoietin, which induces differentiation of CDs thymocytes into regulatory T cells within the thymus medulla. Thymic B lymphocytes produce immunoglobulins and immunoregulating hormones, including thymosin. Modulation in T cell and naive T cells decrement due to thymus deformity induce alteration in the secretion of various inflammatory factors, resulting in multiple diseases. Influenza virus activates thymic CD4+ CD8+ thymocytes and a large amount of IFNγ. IFNs limit virus spread, enhance macrophages' phagocytosis, and promote the natural killer cell restriction activity against infected cells. Th2 lymphocytes-produced cytokine IL-4 can bind to antiviral INFγ, decreasing the cell susceptibility and downregulating viral receptors. COVID-19 epitopes (S, M, and N proteins) with ≥90% identity to the SARS-CoV sequence have been predicted. These epitopes trigger immunity for antibodies production. Boosting the immune system by improving thymus function can be a therapeutic strategy for preventing virus-related diseases. This review aims to summarize the endocrine-immunoregulatory functions of the thymus and the underlying mechanisms in the prevention of COVID-19.

Keywords: dynamic programming; hedging; post-decision state variable; risk management; transaction costs.

Figure 1

Overall role of the thymus gland in the development of T cells.

Figure 2

Antigen-presenting cells present an antigen complex with a major histocompatibility complex (MHC) to stimulate immature T cells to become either cytotoxic cells (CD8), when the T cell receptor binds to MHC class I, or Th cells (CD4+), when it binds to MHC class II. Once CD4 cells are activated, they will begin proliferation or clonal expansion and differentiate into Th17, Th9, Th1, Th2, and Th22 at the same time; they will secret interleukins that will stimulate a humoral immune response to produce antibodies (IgE), as well as cellular immune response and nonspecific defense by activated cytotoxic T cells and macrophages.

Figure 3

Functions of thymic Hassall’s corpuscles in normal state and after infection with influenza virus. Thymic stromal lymphopoietin (TSLP), a cytokine that is the primary hormone produced by the epithelial cells of Hassall’s corpuscles, was found in the thymus and was responsible for the activation of thymic dendritic cells. Hassall’s corpuscles secrete TSLP-inducing dendritic cells to induce and generate CD4+ CD8+ CD25+ regulatory T cells within the thymus. Thymic plasmacytoid dendritic cells express IL-23 receptors. Transforming growth factor alpha (TGF-α) was identified in medullary human thymic epithelial (TE) cells and thymic Hassall’s corpuscles while epidermal growth factor receptor (EGF-R) was concentrated to TE cells through the thymus tissue. Hence, TGF-α and EGF are crucial regulatory precursors for the synthesis of TE cell-derived cytokines in the thymus. The human thymus shows the existence of antibodies IgG, IgA, IgM, IgD, and IgE, which are secretory constituents in Hassall’s corpuscles. There is a strong connection between the amounts of IgA and secretory components in the cells of Hassall’s corpuscles, and the thymus may have to be considered as an active portion of the secretory-IgA system of Hassall’s corpuscles. The influenza virus activates thymic CD4+ CD8+ thymocytes, leading to the secretion of a large amount of interferon IFNγ.

Figure 4

Types and roles of thymus gland hormones. The thymus produces immunoregulating hormones such as thymosin, and its family includes prothymosin alpha, thymosin alpha 1, thymosin beta-4 and thymosin beta-10, thymuline, and thymopoietin.

Figure 5

T alpha 1 cells and functional outcomes by targeting dendritic cells. Tα1 cells can modulate dendritic cell (DC) function. DCs express variable receptors for communications to induce T helper type 1 (Th1), T helper type2 (Th2), and regulatory T cells (Treg) priming antigen-specific T cell activation. Tα1 cells convert resting DCs into cells capable of promoting the polarization and differentiation of naive T cells.

Figure 6

Effect of Tα1 on cells and pathways of the immune system. Tα1 can trigger multiple downstream pathways with distinct types of immune cells, pro/anti-inflammatory cytokine, and induce an immune response by Toll-like receptor (TLR) expression and cytokine production, leading to the initiation of a subsequent phase of immunity.

Figure 7

Immune response pathway against MERS-CoV infection. Macrophages present virus antigens to a naive T cell. This process is followed by the activation of T cells. Differentiation induces the production of cytokines specific to the different T cell subsets (Th1, Th2), resulting in the massive production of cytokines. Due to natural killer (NK) cells and cytotoxic T cell (CD8 T cell) activation, these cells produce effective mediators, such as IFNγ and granzyme, to clear a viral infection.