Thymic nurse cell

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Thymic nurse cells (TNCs) are large epithelial cells found in the cortex of the thymus and also in cortico-medullary junction. [1] They have their own nucleus and are known to internalize thymocytes through extensions of plasma membrane. [1] [2] 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. [2]

Cortex (anatomy)

In anatomy and zoology, the cortex is the outermost layer of an organ. Organs with well-defined cortical layers include kidneys, adrenal glands, ovaries, the thymus, and portions of the brain, including the cerebral cortex, the best-known of all cortices.

Thymus organ of the immune system

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is composed of two identical lobes and is located anatomically in the anterior superior mediastinum, in front of the heart and behind the sternum. Histologically, each lobe of the thymus can be divided into a central medulla and a peripheral cortex which is surrounded by an outer capsule. The cortex and medulla play different roles in the development of T cells. Cells in the thymus can be divided into thymic stromal cells and cells of hematopoietic origin. Developing T cells are referred to as thymocytes and are of hematopoietic origin. Stromal cells include epithelial cells of the thymic cortex and medulla, and dendritic cells.

Cell nucleus A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated.

In cell biology, the nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotes usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many.

Structure and function

Thymic nurse cells (TNCs) are a sub-population of cortical thymic epithelial cells (cTECs). [3] pH91, which is a TNC-specific monoclonal antibody, that can be used to identify TNCs. [2] Thymic nurse cells express both MHC Class I and II antigens, [3] [4] and are found in the cortico-medullary junction in addition to the cortex of the thymus.

Epithelial reticular cells, or epithelioreticular cells(ERC), some called thymic epithelial cell (TEC), are a structure in both the cortex and medulla of the thymus. However, histologically, they are more easily identified in the medulla. These cells contain secretory granules which are thought to contain the thymic hormones.

Monoclonal antibody monospecific antibody that is made by identical immune cells that are all clones of a unique parent cell

Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies can have monovalent affinity, in that they bind to the same epitope. In contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different plasma cell lineages. Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one single monoclonal antibody to two epitopes.

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. [2] 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. [2]

Cytokeratin

Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate filaments, which help cells resist mechanical stress. Expression of these cytokeratins within epithelial cells is largely specific to particular organs or tissues. Thus they are used clinically to identify the cell of origin of various human tumors.

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. [2] The enclosed thymocytes have been found to remain intact and retain both metabolic and mitotic activities despite lacking any contact with the extracellular environment. [5] [6]

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. [7] [2] 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. [7] 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. [7] 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. [8]

Lysosome small lytic vacuole with cell cycle-independent morphology, found in most animal cells; contains a variety of hydrolases, most of which have their maximal activities in the pH range 5-6

A lysosome is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins, and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, cell signaling, and energy metabolism.

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. [2] [9] [10]

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a given T cell can interact with both the self-major histocompatibility complex molecule and the foreign peptide that is bound to it, but will recognize and respond to the antigen, only when it is bound to a particular MHC molecule.

Antigen-presenting cell Any cell that assists in the production of immune responses by presenting antigen; especially any of several types of cell with monocytic lineage that present antigen in association with class II MHC molecules, to helper T lymphocytes.

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen complexed with major histocompatibility complexes (MHCs) on their surfaces; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-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. [9] 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. [9]

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. [2] [8] [11]

Thymocytes uptake

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. [3]

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. [2]

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. [3]

Thymocytes within TNC

Incubation of TNC at 37°C in tissue culture releases thymocytes (TNC-T) present within it. [12] [13] 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). [12] [14] [15] Unlike ET, mouse TNC-T cells proliferate following stimulation with alloantigen [12] [13] [14] [15] , mitogen [13] and help B cell make antibody [14] 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 [15] . Based on the observation that TNC harbor functionally mature population of TNC-T [12] [13] [14] [15] 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. [13] [14]

Notes

  1. 1 2 Ritter, M. A., C. A. Sauvage, and S. F. Cotmore. "The human thymus microenvironment: in vivo identification of thymic nurse cells and other antigenically-distinct subpopulations of epithelial cells." Immunology 44.3 (1981): 439.
  2. 1 2 3 4 5 6 7 8 9 10 Hendrix, Tonya M. et al. “Thymic Nurse Cells Exhibit Epithelial Progenitor Phenotype and Create Unique Extra-Cytoplasmic Membrane Space for Thymocyte Selection.” Cellular immunology 261.2 (2010): 81–92. PMC. Web. 6 Feb. 2017
  3. 1 2 3 4 Gameiro, Jacy, Patrícia Nagib, and Liana Verinaud. "The thymus microenvironment in regulating thymocyte differentiation." Cell adhesion & migration 4.3 (2010): 382-390.
  4. Nakagawa, Yasushi et al. “Thymic Nurse Cells Provide Microenvironment for Secondary T Cell Receptor Α Rearrangement in Cortical Thymocytes.” Proceedings of the National Academy of Sciences of the United States of America 109.50 (2012): 20572–20577. PMC. Web. 6 Feb. 2017.
  5. Wekerle, H. A. R. T. M. U. T., U. P. Ketelsen, and M. A. R. T. I. N. Ernst. "Thymic nurse cells. Lymphoepithelial cell complexes in murine thymuses: morphological and serological characterization." Journal of Experimental Medicine 151.4 (1980): 925-944.
  6. Ritter, M. A., C. A. Sauvage, and S. F. Cotmore. "The human thymus microenvironment: in vivo identification of thymic nurse cells and other antigenically-distinct subpopulations of epithelial cells." Immunology 44.3 (1981): 439.
  7. 1 2 3 Samms, Michael, et al. "Lysosomal-mediated degradation of apoptotic thymocytes within thymic nurse cells." Cellular immunology 197.2 (1999): 108-115.
  8. 1 2 Reyes García, María Guadalupe, and Fernando García Tamayo. "The importance of the nurse cells and regulatory cells in the control of T lymphocyte responses." BioMed Research International 2013 (2012).
  9. 1 2 3 Martinez, Marcia, et al. "Thymic nurse cell multicellular complexes in HY-TCR transgenic mice demonstrate their association with MHC restriction." Experimental Biology and Medicine 232.6 (2007): 780-788.
  10. Ohigashi, Izumi, Mina Kozai, and Yousuke Takahama. "Development and developmental potential of cortical thymic epithelial cells." Immunological reviews 271.1 (2016): 10-22.
  11. C Guyden, J., et al. "Thymic Nurse Cells Participate in Heterotypic Internalization and Repertoire Selection of Immature Thymocytes; Their Removal from the Thymus of Autoimmune Animals May be Important to Disease Etiology." Current Molecular Medicine 15.9 (2015): 828-835.
  12. 1 2 3 4 Vakharia D.D."Demonstration of keratin filaments in thymic nurse cells (TNC) and alloreactivity of TNC-T cell."Thymus 5.1(1983):43-52.
  13. 1 2 3 4 5 Dilip Dwarkadas Vakharia."Thymic Nurse Cells in the Mouse." PhD thesis, UCL, UK (1983):1-205.https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759963
  14. 1 2 3 4 5 Vakharia DD, Mitchison NA. "Helper T cell activity demonstrated by thymic nurse T cells (TNC-T)." Immunology 51.7(1984):269-273.
  15. 1 2 3 4 Penninger J, Hála K, Wick G. "Inrathymic nurse cell lymphocytes can induce a specific graft-versus-host reaction." J Exp Med 172.2(1990): 521-529.

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