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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.^[3] LFA-1 has two subunits designated as the alpha subunit and beta subunit.^[2] The alpha subunit was named aL in 1983.^[2] The alpha subunit is designated CD11a; and the beta subunit, unique to leukocytes, is beta-2 or CD18.^[2] The ICAM binding site is on the alpha subunit.^[5] The general binding region of the alpha subunit is the I-domain. Due to the presence of a divalent cation site in the I-domain, the specific binding site is often referred to as the metal-ion dependent adhesion site (MIDAS).^[5]

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]

References

^ ^a ^b Lackie JM (2010). A dictionary of biomedicine (1st ed.). Oxford: Oxford University Press. ISBN 9780191727948. OCLC 663104793.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ Ley K (2007). Adhesion molecules : function and inhibition. Basel: Birkhauser. ISBN 9783764379759. OCLC 261225084.
^ ^a ^b ^c ^d Cammack R (2006). Oxford dictionary of biochemistry and molecular biology (Rev. ed.). Oxford: Oxford University Press. ISBN 9780191727641. OCLC 743217704.
^ Verma NK, Kelleher D (August 2017). "Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program". Journal of Immunology. 199 (4): 1213–1221. doi:10.4049/jimmunol.1700495. PMID 28784685.
^ ^a ^b ^c ^d ^e ^f ^g Dömling A (2013). Protein-protein interactions in drug discovery. Weinheim: Wiley-VCH. ISBN 9783527648238. OCLC 828743731.
^ ^a ^b ^c Akbari H, Zadeh MM (January 2001). "Leukocyte adhesion deficiency". Indian Journal of Pediatrics. 68 (1): 77–9. doi:10.1007/bf02728867. PMID 11237241. S2CID 11336052.
^ Anderson DC, Springer TA (1987). "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins". Annual Review of Medicine. 38: 175–94. doi:10.1146/annurev.me.38.020187.001135. PMID 3555290.

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

[:0-1] Lackie JM (2010). A dictionary of biomedicine (1st ed.). Oxford: Oxford University Press. ISBN 9780191727948. OCLC 663104793.

[:1-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ Ley K (2007). Adhesion molecules : function and inhibition. Basel: Birkhauser. ISBN 9783764379759. OCLC 261225084.

[:2-3] Cammack R (2006). Oxford dictionary of biochemistry and molecular biology (Rev. ed.). Oxford: Oxford University Press. ISBN 9780191727641. OCLC 743217704.

[4] Verma NK, Kelleher D (August 2017). "Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program". Journal of Immunology. 199 (4): 1213–1221. doi:10.4049/jimmunol.1700495. PMID 28784685.

[:3-5] ^ ^a ^b ^c ^d ^e ^f ^g Dömling A (2013). Protein-protein interactions in drug discovery. Weinheim: Wiley-VCH. ISBN 9783527648238. OCLC 828743731.

[:4-6] Akbari H, Zadeh MM (January 2001). "Leukocyte adhesion deficiency". Indian Journal of Pediatrics. 68 (1): 77–9. doi:10.1007/bf02728867. PMID 11237241. S2CID 11336052.

[7] Anderson DC, Springer TA (1987). "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins". Annual Review of Medicine. 38: 175–94. doi:10.1146/annurev.me.38.020187.001135. PMID 3555290.

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+'''Lymphocyte function-associated antigen 1''' ('''LFA-1''') is an [[integrin]] found on [[lymphocyte]]s and other leukocytes.<ref name=":0">{{Cite book|title=A dictionary of biomedicine | vauthors = Lackie JM |date=2010|publisher=Oxford University Press|isbn=9780191727948|edition= 1st|location=Oxford|oclc=663104793}}</ref> 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.<ref name=":1">{{Cite book|title=Adhesion molecules : function and inhibition|url=https://archive.org/details/adhesionmolecule0000unse_x7m0|url-access=registration|date=2007|publisher=Birkhauser| last = Ley | first = Klaus | name-list-style = vanc |isbn=9783764379759|location=Basel|oclc=261225084}}</ref>  Additionally, LFA-1 is involved in the process of [[cytotoxic T cell]] mediated killing as well as antibody mediated killing by granulocytes and monocytes.<ref name=":2">{{Cite book | last = Cammack | first = Richard | name-list-style = vanc |title=Oxford dictionary of biochemistry and molecular biology|date=2006|publisher=Oxford University Press |isbn=9780191727641|edition= Rev.|location=Oxford|oclc=743217704}}</ref> As of 2007, LFA-1 has 6 known ligands: [[ICAM-1]], [[ICAM2|ICAM-2]], ICAM-3, ICAM-4, ICAM-5, and JAM-A.<ref name=":1" /> LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation.<ref>{{cite journal | vauthors = Verma NK, Kelleher D | title = Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program | journal = Journal of Immunology | volume = 199 | issue = 4 | pages = 1213–1221 | date = August 2017 | pmid = 28784685 | doi = 10.4049/jimmunol.1700495 | doi-access = free }}</ref> LFA-1 belongs to the [[integrin]] superfamily of adhesion molecules.<ref name=":0" />
-'''Lymphocyte function-associated antigen 1''' ('''LFA-1''') is found on all [[T-cells]] and also on [[B-cells]], [[macrophages]], [[neutrophils]] and [[NK cells]] and is involved in recruitment to the site of infection. It binds to [[ICAM-1]] on [[antigen-presenting cells]] and functions as an adhesion molecule.  LFA-1 is the first to bind T-cells to antigen-presenting cells and initially binds weakly. A signal from the T-cell receptor and/or the cytokine receptor changes the conformation and prolongs the cell contact, allowing the T-cell to proliferate. LFA-1/ICAM-1 interaction has recently been shown to be important for T cell-T cell interactions, leading to further T cell differentiation.<ref>Verma NK, Kelleher D. Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program. J Immunol. 2017 Aug 15;199(4):1213-1221. doi:[http://www.jimmunol.org/content/199/4/1213.long 10.4049/jimmunol.1700495]. Review. PubMed {{PMID|28784685}}.</ref>
+== Structure ==
-LFA-1 is part of the family of leukocyte [[integrin]]s that are recognised by their common β-chains (β2, [[CD18]]). LFA-1 also has a distinct α-chain (αL, [[CD11a]]).<ref>Mancuso RV, Welzenbach K, Steinberger P, Krähenbühl S, Weitz-Schmidt G. Downstream effect profiles discern different mechanisms of integrin αLβ2 inhibition. Biochem Pharmacol. 2016 Nov 1;119:42-55. doi:[http://www.sciencedirect.com/science/article/pii/S0006295216302623?via%3Dihub 10.1016/j.bcp.2016.09.002]. Epub 2016 Sep 6. PubMed {{PMID|27613223}}.</ref>
+LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits.<ref name=":2" /> LFA-1 has two subunits designated as the alpha subunit and beta subunit.<ref name=":1" /> The alpha subunit was named aL in 1983.<ref name=":1" /> The alpha subunit is designated [[CD11a]]; and the beta subunit, unique to leukocytes, is beta-2 or [[CD18]].<ref name=":1" /> The ICAM binding site is on the alpha subunit.<ref name=":3">{{cite book|title=Protein-protein interactions in drug discovery|date=2013|publisher=Wiley-VCH| last = Dömling | first = Alexander | name-list-style = vanc |isbn=9783527648238|location=Weinheim|oclc=828743731}}</ref> The general binding region of the alpha subunit is the I-domain. Due to the presence of a divalent cation site in the I-domain, the specific binding site is often referred to as the metal-ion dependent adhesion site (MIDAS).<ref name=":3" />
+== Activation ==
-LFA-1 has also been found in a soluble form.<ref name="pmid20826754">{{cite journal | vauthors = Gjelstrup LC, Boesen T, Kragstrup TW, Jørgensen A, Klein NJ, Thiel S, Deleuran BW, Vorup-Jensen T | title = Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure | journal = Journal of Immunology | volume = 185 | issue = 7 | pages = 4154–68 | year = 2010 | pmid = 20826754 | doi = 10.4049/jimmunol.1000952 }}</ref>
+In an inactive state, LFA-1 rests in a bent conformation and has a low affinity for ICAM binding.<ref name=":3" /> This bent conformation conceals the MIDAS. [[Chemokine]]s stimulate the activation process of LFA-1.<ref name=":3" /> The activation process begins with the activation of [[Rap1]], an intracellular g-protein.<ref name=":1" /> Rap1 assists in breaking the constraint between the alpha and beta subunits of LFA-1.<ref name=":1" /> This induces an intermediate extended conformation.<ref name=":1" /> The conformational change stimulates a recruitment of proteins to form an activation complex. The activation complex further destabilizes the alpha and beta subunits.<ref name=":1" /> 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.<ref name=":3" /> 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.<ref name=":3" /> 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.<ref name=":3" />
-==See also==
+== Discovery ==
+Early discovery of cellular adhesion molecules involved the use of monoclonal antibodies to inhibit cellular adhesion processes.<ref name=":1" /> The antigen that bound to the monoclonal antibodies was identified as an important molecule in cellular recognition processes.<ref name=":1" /> 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.<ref name=":1" /> LFA-1, a leukocyte integrin, was first discovered by Timothy Springer in mice in the 1980s.<ref name=":1" />
+== Leukocyte Adhesion Deficiency (LAD) ==
+[[Leukocyte adhesion deficiency]] is an immunodeficiency caused by the absence of key adhesion surface proteins, including LFA-1.<ref name=":4">{{cite journal | vauthors = Akbari H, Zadeh MM | title = Leukocyte adhesion deficiency | journal = Indian Journal of Pediatrics | volume = 68 | issue = 1 | pages = 77–9 | date = January 2001 | pmid = 11237241 | doi = 10.1007/bf02728867 | s2cid = 11336052 }}</ref> LAD is a genetic defect caused by autosomal recessive genes.<ref name=":4" /> The deficiency causes ineffective migration and phagocytosis for impacted leukocytes.<ref name=":2" /> Patients with LAD also have poorly functioning neutrophils.<ref name=":1" /> [[Leukocyte adhesion deficiency-1|LAD1]], a subtype of LAD, is caused by a lack of integrins that contain the beta subunit, including LFA-1.<ref name=":2" /> LAD1 is characterized by recurring bacterial infection, delayed (>30 days) separation of umbilical cord, ineffective wound healing and pus formation, and granulocytosis.<ref>{{cite journal | vauthors = Anderson DC, Springer TA | title = Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins | journal = Annual Review of Medicine | volume = 38 | pages = 175–94 | date = 1987 | pmid = 3555290 | doi = 10.1146/annurev.me.38.020187.001135 }}</ref> LAD1 is caused by low expression of CD11 and CD18. CD18 is found on chromosome 21 and CD11 is found on chromosome 16.<ref name=":4" />
+== See also ==
 * [[Leukocyte adhesion deficiency]]
 * [[Lifitegrast]], a drug that blocks LFA-1 from binding to ICAM-1
-==Further reading==
+== References ==
+{{Reflist}}
+== Further reading ==
+{{refbegin}}
 * 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
+* {{cite journal | vauthors = Davignon D, Martz E, Reynolds T, Kürzinger K, Springer TA | title = Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 7 | pages = 4535–9 | date = July 1981 | pmid = 7027264 | pmc = 319826 | doi = 10.1073/pnas.78.7.4535 | bibcode = 1981PNAS...78.4535D | doi-access = free }}
+* {{cite journal | vauthors = Gérard A, Khan O, Beemiller P, Oswald E, Hu J, Matloubian M, Krummel MF | title = Secondary T cell-T cell synaptic interactions drive the differentiation of protective CD8+ T cells | journal = Nature Immunology | volume = 14 | issue = 4 | pages = 356–63 | date = April 2013 | pmid = 23475183 | pmc = 3962671 | doi = 10.1038/ni.2547 }}
+{{refend}}
+== External links ==
-==References==
-{{Reflist}}
-==External links==
 * {{MeshName|LFA-1}}
-*{{cite journal |author=Davignon D, Martz E, Reynolds T, Kürzinger K, [[Springer TA]] |title=Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=78 |issue=7 |pages=4535–9 |year=1981 |pmid=7027264 |doi=10.1073/pnas.78.7.4535 |pmc=319826}}
 *[https://web.archive.org/web/20110704224705/http://cmkb.cellmigration.org/report.cgi?report=compl_overview&compl_acc=cc00000033 ITGAL ITGB2] Info with links in the [http://www.cellmigration.org/index.shtml Cell Migration Gateway]
-*{{cite journal |author1=Audrey Gérard |author2=Omar Khan |author3=Peter Beemiller |author4=Erin Oswald |author5=Joyce Hu |author6=Mehrdad Matloubian |author7=Matthew F Krummel |title=Secondary T cell–T cell synaptic interactions drive the differentiation of protective CD8+ T cells |journal=Nature Immunology |volume=14 |pages=356–363 |year=2013 |doi=10.1038/ni.2547 |pmid=23475183 |pmc=3962671}}
 {{Cell adhesion molecules}}
 {{Integrins}}