Alternative titles; symbols
HGNC Approved Gene Symbol: ITGAL
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:30,472,742-30,523,185 (from NCBI)
Larson et al. (1989) isolated clones corresponding to the LFA1-alpha subunit from a size-selected lambda-gt10 cDNA library constructed from PMA-stimulated myeloid cells. The protein contains a 25-amino acid hydrophobic signal sequence, a 1,063-amino acid extracellular domain, a 29-amino acid transmembrane domain, and a 53-amino acid cytoplasmic tail. The extracellular region contains 7 repeats. The LFA1-alpha protein shares 36% identity with the alpha subunits of MAC1 (ITGAM; 120980) and p150,95 (ITGAX; 151510); all 3 of these proteins contain an approximately 200-amino acid insert in the N terminus relative to other integrin alpha subunits. Northern blot analysis detected expression of a 5.5-kb transcript in lymphoid and myeloid cells but not in bladder carcinoma.
Lymphocyte function-associated antigen-1 (LFA1) is a dimer consisting of CD11A (ITGAL) and a beta subunit (ITGB2; 600065). ITGB2 also associates with other alpha chains, e.g., with ITGAM (120980) to form MAC1 and with ITGAX (151510) to form p150,95. LFA1 is expressed on lymphocytes and phagocytic cells. The LFA1 molecule is involved in the adhesion of cytotoxic T cells to their target cells. Patients with LFA1 immunodeficiency disease (116920) have recurrent life-threatening infections, show deficiency of the beta chain of all 3 molecules, LFA1, Mac1 (macrophage antigen-1), and p150,95, and display profound defects in adhesion-dependent granulocyte, monocyte, and B- and T-lymphocyte functions. The alpha subunits were designated by Marlin et al. (1986) as alpha-L for LFA1, alpha-M for Mac1, and alpha-X for p150,95.
Marlin et al. (1986) showed that the genetic defect in LFA1 immunodeficiency disease resides in the common beta subunit of these 3 molecules. Furthermore, they were able to demonstrate that the beta subunit is coded by chromosome 21, whereas the unique alpha subunit of LFA1 is coded by chromosome 16. These results were obtained by human-mouse T-cell fusion studies. Human LFA1 alpha and mouse beta subunits joined in the interspecies hybrid cells to form alpha-beta complexes. Surface expression of the alpha, but not of the beta, subunit of patient cells was restored by the formation of interspecies complexes. These findings showed that the LFA1 alpha subunit in genetically deficient cells is competent for surface expression in the presence of an appropriate beta subunit.
In the serum of a multiply transfused patient with systemic lupus erythematosus (152700), Pischel et al. (1987) identified an antibody directed at determinants of the LFA1 alpha-chain. Since the serum did not immunoprecipitate LFA1 from autologous cells, even though LFA1 molecules were present, the serum identified 2 serologic phenotypes of LFA1. The serum reacted with cells from 95% of normal individuals.
Lu and Cyster (2002) studied the mechanisms that control localization of marginal zone B cells. They demonstrated that marginal zone B cells express elevated levels of the integrins LFA1 and alpha-4-beta-1 (see 192975 and 135630) and that the marginal zone B cells bind to the ligands ICAM1 (147840) and VCAM1 (192225). These ligands are expressed within the marginal zone in a lymphotoxin-dependent manner. Combined inhibition of LFA1 and alpha-4-beta-1 causes a rapid and selective release of B cells from the marginal zone. Furthermore, lipopolysaccharide-triggered marginal zone B cell relocalization involves downregulation of integrin-mediated adhesion. Lu and Cyster (2002) concluded that their studies identified key requirements for marginal zone B cell localization and established a role for integrins in peripheral lymphoid tissue compartmentalization.
Anikeeva et al. (2005) found that LFA1 engagement could be replaced by other adhesion mechanisms, such as CD2 (186990)-CD58 (LFA3; 153420) interaction, in antigen-induced cytotoxic T-lymphocyte granule polarization and degranulation, but that LFA1 engagement was indispensable for effective target cell lysis by the released granules. LFA1-mediated adhesion to glass-supported bilayers resulted in a much larger junction area and formation of a peripheral supramolecular activation cluster compared with CD2-mediated adhesion. Anikeeva et al. (2005) concluded that LFA1 delivers a distinct signal essential for directing released granules to antigen-bearing target cells to mediate their destruction.
By in situ hybridization, Corbi et al. (1988) demonstrated that the genes encoding the alpha subunits of LFA1, Mac1, and p150,95, all of which play a part in leukocyte adhesion, constitute a cluster located on 16p13.1-p11. Callen et al. (1991) narrowed the localization to 16p11.2.
Kim et al. (2003) investigated cytoplasmic conformational changes in the integrin LFA1 (alpha-L; beta-2, 600065) in living cells by measuring fluorescence resonance energy transfer between cyan fluorescent protein-fused and yellow fluorescent protein-fused alpha-L and beta-2 cytoplasmic domains. In the resting state these domains were close to each other, but underwent significant spatial separation upon either intracellular activation of integrin adhesiveness (inside-out signaling) or ligand binding (outside-in signaling). Thus, bidirectional integrin signaling is accomplished by coupling extracellular conformational changes to an unclasping and separation of the alpha and beta cytoplasmic domains, which Kim et al. (2003) noted as a distinctive mechanism for transmitting information across the plasma membrane.
Interactions between LFA1 and intercellular adhesion molecules are important in the pathogenesis of psoriasis (see 177900). Lebwohl et al. (2003) studied the therapeutic effects of efalizumab, a humanized monoclonal antibody that binds to the alpha subunit of LFA1 and inhibits the activation of T cells, in subjects with psoriasis. A significant improvement in plaque psoriasis was observed in subjects with moderate to severe disease. Extending treatment from 12 to 24 weeks resulted in both maintenance and improvement of responses.
Anikeeva, N., Somersalo, K., Sims, T. N., Thomas, V. K., Dustin, M. L., Sykulev, Y. Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proc. Nat. Acad. Sci. 102: 6437-6442, 2005. [PubMed: 15851656] [Full Text: https://doi.org/10.1073/pnas.0502467102]
Callen, D. F., Chen, L. Z., Nancarrow, J., Whitmore, S. A., Apostolou, S., Thompson, A. D., Lane, S. A., Stallings, R. L., Hildebrand, C. E., Harris, P. G., Sutherland, G. R. Current state of the physical map of human chromosome 16. (Abstract) Cytogenet. Cell Genet. 58: 1998 only, 1991.
Corbi, A. L., Larson, R. S., Kishimoto, T. K., Springer, T. A., Morton, C. C. Chromosomal location of the genes encoding the leukocyte adhesion receptors LFA-1, Mac-1 and p150,95: identification of a gene cluster involved in cell adhesion. J. Exp. Med. 167: 1597-1607, 1988. [PubMed: 3284962] [Full Text: https://doi.org/10.1084/jem.167.5.1597]
Fischer, A., Durandy, A., Sterkers, G., Griscelli, C. Role of the LFA-1 molecule in cellular interactions required for antibody production in humans. J. Immun. 136: 3198-3203, 1986. [PubMed: 3514755]
Kim, M., Carman, C. V., Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301: 1720-1725, 2003. [PubMed: 14500982] [Full Text: https://doi.org/10.1126/science.1084174]
Larson, R. S., Corbi, A. L., Berman, L., Springer, T. Primary structure of the leukocyte function-associated molecule-1 alpha subunit: an integrin with an embedded domain defining a protein superfamily. J. Cell Biol. 108: 703-712, 1989. [PubMed: 2537322] [Full Text: https://doi.org/10.1083/jcb.108.2.703]
Lebwohl, M., Tyring, S. K., Hamilton, T. K., Toth, D., Glazer, S., Tawfik, N. H., Walicke, P., Dummer, W., Wang, X., Garovoy, M. R., Pariser, D. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. New Eng. J. Med. 349: 2004-2013, 2003. [PubMed: 14627785] [Full Text: https://doi.org/10.1056/NEJMoa030002]
Lu, T. T., Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297: 409-412, 2002. [PubMed: 12130787] [Full Text: https://doi.org/10.1126/science.1071632]
Marlin, S. D., Morton, C. C., Anderson, D. C., Springer, T. A. LFA-1 immunodeficiency disease: definition of the genetic defect and chromosomal mapping of alpha and beta subunits of the lymphocyte function-associated antigen 1 (LFA-1) by complementation in hybrid cells. J. Exp. Med. 164: 855-867, 1986. [PubMed: 3528378] [Full Text: https://doi.org/10.1084/jem.164.3.855]
Pischel, K. D., Marlin, S. D., Springer, T. A., Woods, V. L., Jr., Bluestein, H. G. Polymorphism of lymphocyte function-associated antigen-1 demonstrated by a lupus patient's alloantiserum. J. Clin. Invest. 79: 1607-1614, 1987. [PubMed: 2438304] [Full Text: https://doi.org/10.1172/JCI112996]
Sanchez-Madrid, F., Nagy, J., Robbins, E., Simon, P., Springer, T. A. A human leukocyte differentiation antigen family with distinct alpha subunits and a common beta subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J. Exp. Med. 158: 1785-1803, 1983. [PubMed: 6196430] [Full Text: https://doi.org/10.1084/jem.158.6.1785]