Lymphocyte function-associated antigen 1
Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes.[1] LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes.[2] Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes.[3] As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A.[2] LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation.[4] LFA-1 belongs to the integrin superfamily of adhesion molecules.[1]
Structure
LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits.
Activation
In an inactive state, LFA-1 rests in a bent conformation and has a low affinity for ICAM binding.[5] This bent conformation conceals the MIDAS. Chemokines stimulate the activation process of LFA-1.[5] The activation process begins with the activation of Rap1, an intracellular g-protein.[2] Rap1 assists in breaking the constraint between the alpha and beta subunits of LFA-1.[2] This induces an intermediate extended conformation.[2] The conformational change stimulates a recruitment of proteins to form an activation complex. The activation complex further destabilizes the alpha and beta subunits.[2] Chemokines also stimulate an I-like domain on the beta subunit, which causes the MIDAS site on the beta subunit to bind to glutamate on the I domain of the alpha subunit.[5] This binding process causes the beta subunit to pull down the alpha 7 helix of the I domain, exposing and opening up the MIDAS site on the alpha subunit for binding.[5] This causes LFA-1 to undergo a conformational change to the fully extended conformation. The process of activating LFA-1 is known as inside out signaling, which causes LFA-1 to shift from low affinity to high affinity by opening the ligand-binding site.[5]
Discovery
Early discovery of cellular adhesion molecules involved the use of monoclonal antibodies to inhibit cellular adhesion processes.[2] The antigen that bound to the monoclonal antibodies was identified as an important molecule in cellular recognition processes.[2] These experiments yielded the protein name “integrin” as a description of the proteins' integral role in cellular adhesion processes and the transmembrane association between the extracellular matrix and the cytoskeleton.[2] LFA-1, a leukocyte integrin, was first discovered by Timothy Springer in mice in the 1980s.[2]
Leukocyte Adhesion Deficiency (LAD)
Leukocyte adhesion deficiency is an immunodeficiency caused by the absence of key adhesion surface proteins, including LFA-1.[6] LAD is a genetic defect caused by autosomal recessive genes.[6] The deficiency causes ineffective migration and phagocytosis for impacted leukocytes.[3] Patients with LAD also have poorly functioning neutrophils.[2] LAD1, a subtype of LAD, is caused by a lack of integrins that contain the beta subunit, including LFA-1.[3] LAD1 is characterized by recurring bacterial infection, delayed (>30 days) separation of umbilical cord, ineffective wound healing and pus formation, and granulocytosis.[7] LAD1 is caused by low expression of CD11 and CD18. CD18 is found on chromosome 21 and CD11 is found on chromosome 16.[6]
See also
- Leukocyte adhesion deficiency
- Lifitegrast, a drug that blocks LFA-1 from binding to ICAM-1
References
Further reading
- Janeway, Travers, Walport, Shlomchik, Immunobiology 6th ed. (2005) Garland Science:NY
- Parham, Peter, The Immune System 3rd ed. (2009) Garland Science: London and New York
- Davignon D, Martz E, Reynolds T, Kürzinger K, Springer TA (July 1981). "Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing". Proceedings of the National Academy of Sciences of the United States of America. 78 (7): 4535–9. PMID 7027264.
- Gérard A, Khan O, Beemiller P, Oswald E, Hu J, Matloubian M, Krummel MF (April 2013). "Secondary T cell-T cell synaptic interactions drive the differentiation of protective CD8+ T cells". Nature Immunology. 14 (4): 356–63. PMID 23475183.
External links
- LFA-1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- ITGAL ITGB2 Info with links in the Cell Migration Gateway