Lymphocyte homing receptor

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Lymphocyte homing receptors are cell adhesion molecules [1] expressed on lymphocyte cell membranes that recognize addressins on target tissues. Lymphocyte homing refers to adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs. [2] These diverse tissue-specific adhesion molecules on lymphocytes (homing receptors) and on endothelial cells (vascular addressins) contribute to the development of specialized immune responses.

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Free lymphocytes constantly recirculate in blood after their re-entry from lymphoid tissue, via lymphatic and thoracic ducts. This happens so that the full repertoire of antigenic specificities of lymphocytes is continuously represented throughout the body. Homing happens in tissue-specific manner—e.g. B lymphocytes migrate better to mucosa-associated lymphoid tissue (Peyer's patches), and T lymphocytes preferentially to the peripheral lymph nodes. [3]

The process of lymphocyte homing is deliberate, mediated by lymphocyte-endothelial recognition mechanisms that enable antigen-specific immune responses. Lymphocyte homing receptor control of organ-specific lymphocyte trafficking is thought to prevent autoreactivity in immune responses during B and T cell differentiation. [2] Recently, lymphocyte homing has become a topic of interest for investigation of treatments for multiple sclerosis, type 1 diabetes mellitus, leukemia, and psoriasis. [4]

Homing mechanisms

Naive lymphocyte homing

Naive lymphocytes are able to circulate into secondary lymphoid tissues, Peyer’s patches, lymph nodes, and the spleen. Because they have not yet been exposed to antigen, these lymphocytes are undifferentiated and express few homing receptors. [4]

High endothelial venules (HEVs) are cells found in secondary lymphoid organs that express large quantities of cell adhesion molecules, enabling undifferentiated lymphocytes to bind. [2] After entering lymph nodes and Peyer’s patches via HEVs, naive T and B cells are exposed to antigen circulating in lymph and differentiate to contribute to the adaptive immune response. HEVs develop from cytokine production after exposure to antigen and express adhesion molecules from the selectin family, mucin-like family, and the Ig superfamily. [5] Naive lymphocyte extravasation into Peyer’s patches is often mediated by L-selectin and limited expression of α4 integrins and other homing receptors prevents these lymphocytes from accessing mucosal effector tissue. [4]

Mature lymphocyte homing

Mature lymphocytes are constantly recirculating in the blood and can traffic to secondary lymphoid tissue as well as target tissue including mucosal tissues of the lamina propria, inflammation, and other extralymphoid immune effector sites. Lymphocyte homing receptor expression is altered by antigen exposure. This function enables the adaptive immune system to specialize an immune response in different parts of the body. [4]

Upon exposure to antigens, lymphocytes lack homing ability during a period of sessile differentiation and cell division, and antigen specific lymphocytes are stored in the spleen for 1–3 days. Subsequently, antigen-stimulated B and T cells express homing receptors particularly for the HEV in initial site of immunization tissue. [2] Furthermore, lymphocytes can alter cell adhesion molecule “activatability” to increase binding ability. [4] Organ-specific lymphocyte homing is important for antigen-specificity and in avoiding autoimmune cross-reactions. [2]

Extravasation of lymphocytes

Lymphocyte homing occurs in four steps leading to extravasation into target tissue; Rolling, activation, activation-dependent “arrest”, and diapedesis. [5] Mediated by lymphocyte receptors and vascular ligand interactions, “tethering” is a reversible linkage that leads to either rolling along the vessel wall or transient immediate arrest. L-selectin is able to mediate vessel adhesion whereas α4 integrins, α4β1 or α4β7, can perform primary or secondary adhesion through a stronger tethering and even contribute to transendothelial migration of lymphocytes. L-selectin, for example, is also able to be cleaved by an enzyme, ensuring proper binding of lymphocytes and allowing release of non-target cells. While attached to the vessel, lymphocytes test target tissue for chemokines and pro-adhesive factors that then prompt “arrest.” In addition to α4 integrins, LFA-1 and Mac-1 mediate the prevention of lymphocyte transendothelial migration into target tissues. While initial adhesion indicates the start of lymphocyte homing, there is regulation of each step of extravasation. [4]

Examples of lymphocyte homing receptors

α4β7 is an α4 integrin class homing receptor that targets lymphocytes in the gut expressing mucosal adhesion molecule-1(MAdCAM-1), mostly expressed in Peyer’s patches. Additionally, α4β1 with the ligand vascular adhesion molecule-1(VCAM-1) function in lymphocyte trafficking and inflammation. [6]

Two other well known examples are CD34 and GLYCAM-1.

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<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

<span class="mw-page-title-main">Selectin</span> Family of cell adhesion molecules

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

<span class="mw-page-title-main">ICAM-1</span> Mammalian protein found in Homo sapiens

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

<span class="mw-page-title-main">L-selectin</span> Mammalian protein found in Homo sapiens

L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the SELL gene. L-selectin belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.

<span class="mw-page-title-main">E-selectin</span>

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

High endothelial venules (HEV) are specialized post-capillary venous swellings characterized by plump endothelial cells as opposed to the usual thinner endothelial cells found in regular venules. HEVs enable lymphocytes circulating in the blood to directly enter a lymph node.

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<span class="mw-page-title-main">Addressin</span> Protein-coding gene in the species Homo sapiens

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is a protein that in humans is encoded by the MADCAM1 gene. The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1, L-selectin, and VLA-4 on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin superfamily and is similar to ICAM-1 and VCAM-1.

Macrophage-1 antigen is a complement receptor ("CR3") consisting of CD11b and CD18.

<span class="mw-page-title-main">Leukocyte extravasation</span>

Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

<span class="mw-page-title-main">Lymphotoxin alpha</span> Protein-coding gene in the species Homo sapiens

Lymphotoxin-alpha (LT-α) formerly known as tumor necrosis factor-beta (TNF-β) is a protein that in humans is encoded by the LTA gene. Belonging to the hematopoietic cell line, LT-α exhibits anti-proliferative activity and causes the cellular destruction of tumor cell lines. As a cytotoxic protein, LT-α performs a variety of important roles in immune regulation depending on the form that it is secreted as. Unlike other members of the TNF superfamily, LT-α is only found as a soluble homotrimer, when found at the cell surface it is found only as a heterotrimer with LTβ.

The following outline is provided as an overview of and topical guide to immunology:

Eugene C. "Gene" Butcher is an American immunologist and a professor of pathology at Stanford University.

Lymph node stromal cells are essential to the structure and function of the lymph node whose functions include: creating an internal tissue scaffold for the support of hematopoietic cells; the release of small molecule chemical messengers that facilitate interactions between hematopoietic cells; the facilitation of the migration of hematopoietic cells; the presentation of antigens to immune cells at the initiation of the adaptive immune system; and the homeostasis of lymphocyte numbers. Stromal cells originate from multipotent mesenchymal stem cells.

Gut-specific homing is the mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response. This process relies on the key interaction between the integrin α4β7 and the addressin MadCAM-1 on the surfaces of the appropriate cells. Additionally, this interaction is strengthened by the presence of CCR9, a chemokine receptor, which interacts with TECK. Vitamin A-derived retinoic acid regulates the expression of these cell surface proteins.

Nasal- or nasopharynx- associated lymphoid tissue (NALT) represents immune system of nasal mucosa and is a part of mucosa-associated lymphoid tissue (MALT) in mammals. It protects body from airborne viruses and other infectious agents. In humans, NALT is considered analogous to Waldeyer's ring.

<span class="mw-page-title-main">Bronchus-associated lymphoid tissue</span>

Bronchus-associated lymphoid tissue (BALT) is a tertiary lymphoid structure. It is a part of mucosa-associated lymphoid tissue (MALT), and it consists of lymphoid follicles in the lungs and bronchus. BALT is an effective priming site of the mucosal and systemic immune responses.

Integrin α4β7 is an integrin heterodimer composed of CD49d (alpha-4) subunit and beta-7 subunit noncovalently linked. LPAM-1 is expressed on the cell surface of leukocytes. This receptor is involved in lymphocyte trafficking pathway to site of inflammation in intestinal tissues.

References

  1. ↑ Lymphocyte+homing+receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. 1 2 3 4 5 Jalkantn, S.; Reichert, R. A.; Gallatin, W. M.; Bargatze, R. F.; Welssman, I. L.; Butcher, E. C. (1986-06-01). "Homing Receptors and the Control of Lymphocyte Migration". Immunological Reviews. 91 (1): 39–60. doi:10.1111/j.1600-065x.1986.tb01483.x. ISSN   1600-065X. PMID   2426181.
  3. ↑ Jutila M A (1994) Function and regulation of leukocyte homing receptors Journal of Leukocyte Biology, vol. 55, pp. 133-140.http://www.jleukbio.org/content/55/1/133.full.pdf
  4. 1 2 3 4 5 6 Butcher, Eugene C.; Picker, Louis J. (1996-04-05). "Lymphocyte Homing and Homeostasis". Science. 272 (5258): 60–67. doi:10.1126/science.272.5258.60. ISSN   0036-8075. PMID   8600538.
  5. 1 2 A., Owen, Judith (2013). Kuby immunology. Punt, Jenni., Stranford, Sharon A., Jones, Patricia P., Kuby, Janis. (7th ed.). New York: W.H. Freeman. ISBN   978-1464119910. OCLC   820117219.
  6. ↑ Yu, Yamei; Zhu, Jianghai; Mi, Li-Zhi; Walz, Thomas; Sun, Hao; Chen, JianFeng; Springer, Timothy A. (2012-01-09). "Structural specializations of α4β7, an integrin that mediates rolling adhesion". J Cell Biol. 196 (1): 131–146. doi:10.1083/jcb.201110023. ISSN   0021-9525. PMC   3255974 . PMID   22232704.
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