Thymic nurse cells (TNCs) are large epithelial cells found in the cortex of the thymus and also in cortico-medullary junction.They have their own nucleus and are known to internalize thymocytes through extensions of plasma membrane. The cell surfaces of TNCs and their cytoplasmic vacuoles express MHC Class I and MHC Class II antigens. The interaction of these antigens with the developing thymocytes determines whether the thymocytes undergo positive or negative selection.
Thymic nurse cells (TNCs) are a sub-population of cortical thymic epithelial cells (cTECs).pH91, which is a TNC-specific monoclonal antibody, that can be used to identify TNCs. Thymic nurse cells express both MHC Class I and II antigens, and are found in the cortico-medullary junction in addition to the cortex of the thymus.
The thymic nurse cells in the cortico-medullary junction express cytokeratin 5 (K5) and cytokeratin 8 (K8), whereas the ones in the cortex express only cytokeratin 8.Thymic nurse cells expressing only cytokeratin 5 have not been identified so far. Hendrix et al. found in their study that one-fourth of the nurse cells isolated from mice were double-positives for K5 and K8, while the rest of them were positive only for K8.
The extensions of plasma membrane from thymic nurse cells form a cage-like structure, which trap (Hendrix et al., 2010) triple positive T cells, αβTCRlowCD4+CD8+ within the spaces formed by the interlocking of the membrane. Some of these T cells retain their mobility and undergo maturation to the developmental stage of αβTCRhighCD69+; they are then released from the TNC complex.The enclosed thymocytes have been found to remain intact and retain both metabolic and mitotic activities despite lacking any contact with the extracellular environment.
Although initially thought to be involved only in positive selection, thymic nurse cells have now been discovered to facilitate negative selection of thymocytes as well.Negative selection refers to the degradation of thymocytes, and has been found to occur through the help of lysosomes. Lysosomes are present near the nucleus in the cytoplasm of TNCs. If the internalized thymocytes are selected for negative selection, vacuoles containing the thymocytes move closer to the area with lysosomes and eventually fuse with the lysosomes. This leads to the degradation of the T cells within the vacuoles. Macrophages have also been found actively moving in and out of the vacuoles inside the TNCs during the times of high apoptotic activity suggesting their involvement in the elimination of negatively selected T lymphocytes.
MHC restriction within TNCs
Whether the thymocytes undergo positive or negative selection is determined through MHC restriction, which refers to the interaction between the αβTCR (αβ T cell receptor) of the T cells and MHC antigens on the antigen-presenting cells.
This role of MHC restriction was observed in a study conducted by Martinez et al. in HY-TCR transgenic mice. Since HY is a male specific antigen, the developing thymocytes would be expected to undergo degradation in males but not in females. However, both males and females were found to contain TNCs.Furthermore, female mice TNCs were found to contain five times more thymocytes than male mice, and less than 4% of them were apoptotic compared to almost 50% in the male TNCs. Also, almost 90% of all thymocytes extracted from the female TNCs were found to be double positives (CD4 + CD8 +), whereas no such phenotype was present within the male thymic nurse cells. Thus, since not all thymocytes internalized by TNCs went through apoptotic pathways, this was used to conclude that thymic nurse cells are involved in MHC restriction process.
Negative selection has been proposed to occur when the αβTCR in developing T cells interact with MHC present on antigen-presenting cells like dendritic cells and macrophages with strong affinities, which then leads T cells down the apoptotic pathway inside the TNCs. Similarly, extremely weak affinities lead to the death of T lymphocytes through neglect. Only intermediate affinity interaction between the αβTCR of the T cells and MHC antigens in the TNCs results in positive selection.
The thymic cortical cells take up early thymocytes migrating from the bone marrow to the thymus and form the thymocyte-TNC complexes. The formation of finger-like projections has been found to facilitate this uptake; which also requires the participation of membrane and cytoskeleton proteins of TECs and thymocytes. Other players that mediate this process are ICAM-1, which is a cell adhesion molecule found on the surface of vacuoles and TNCs, and other extracellular glycoproteins like fibronectin, laminin and type IV collagen, which are produced by TNCs.
Similarly, the cytoplasmic vacuoles present in the cytoplasm near the membrane network also facilitate the uptake of thymocytes that have been negatively selected to undergo apoptosis.
The molecules like gal-3 (Galectin-3) and gal-1(Galectin-1), on the other hand, produce antagonistic effects. They inhibit thymocytes/TEC interaction and affect the movement of thymocytes in and out of TNC, in particular by increasing thymocyte release from TNCs.
Thymocytes within TNC
Incubation of TNC at 37 °C in tissue culture releases thymocytes (TNC-T) present within it. Incubation of TNC at 4 °C or room temperature inhibits release of TNC-T. Incubation of TNC at 37 °C in presence of 0.1% sodium azide prevents the release of TNC-T from within even though the TNC-T are viable. This suggests that metabolic activity of epithelial thymocyte complex is essential for the release of TNC-T.
TNC-T are functionally mature than those external to TNC (ET).Unlike ET, mouse TNC-T cells proliferate following stimulation with alloantigen, mitogen and help B cell make antibody when tested in tissue culture experiments. Chicken TNC-T cells exhibit greater graft vs host reactivity than peripheral blood T cells or ET cells when TNCs from one strain of chicken were placed on egg choriallantoic membrane of another strain of chicken with different MHC antigen. Based on the observation that TNC harbor functionally mature population of TNC-T and the electronmicroscopic studies suggesting that TNCs are localized in close proximity of blood capillaries in both cortex and cortico-medullary region of thymus, Vakharia & Mitchison have hypothesized that TNC-T are potential thymus emigrant cells.
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.
Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.
In the human immune system, central tolerance is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.
A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens but remain tolerant towards the body's own antigens. Positive selection selects cells which are able to bind MHC class I or II molecules with at least a weak affinity. This eliminates those T cells which would be non-functional due to an inability to bind MHC. Negative selection destroys thymocytes with a high affinity for self peptides or MHC. This eliminates cells which would direct immune responses towards self-proteins in the periphery. Negative selection is not 100% effective, and some autoreactive T cells escape and are released into the circulation. Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.
Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.
CD3 is a protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell and T helper cells. It is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the T-cell receptor (TCR) and the CD3-zeta (ζ-chain) to generate an activation signal in T lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.
MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.
Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. Epithelium of small intestine contains approximately 1 IEL per 10 enterocytes. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).
CD83 is a human protein encoded by the CD83 gene.
Gamma delta T cells are T cells that have a distinctive T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, gamma delta (γδ) T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.
Seong Hoe Park is a Korean immunologist and pathologist and a distinguished professor of pathology at the Seoul National University College of Medicine. He served as the chair of the Department of Pathology (2000–2004), the chair of the Graduate Program of Immunology (2002–2006), the president of Center for Animal Resource Development (2004–2006) at Seoul National University. He was the president of the Korean Association of Immunologists (2000–2001). Throughout his career as a T cell immunologist, Park established the theory of T cell-T cell interaction in human thymus, in which T cells expressing MHC class II drive previously unrecognized types of T cells and provide another significant developmental mechanism of T cells.
Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.
Antigen transfer in the thymus is the transmission of self-antigens between thymic Antigen presenting cells (APCs) which contributes to the establishment of T cell central tolerance.
Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.
Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.
Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues. These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells or they deviate them to become T regulatory cells, which suppress self-reactive T cells in the body that escaped negative selection in the thymus. Thus, PGE is crucial for tissues protection against autoimmunity.