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PMID: 21203905 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Biology and function of neuroimmune semaphorins 4A and 4D.

Immunologic research ·Vol. 50 ·No. 1 ·2011-05-00 ·Pages 10-21

Nkyimbeng-Takwi E, Chapoval SP

Abstract

Semaphorins belong to a family of membrane-bound and secreted molecules that regulate the functional activity of axons in the nervous system. Sema4A and Sema4D were the first semaphorins also found to be expressed in immune cells and were, therefore, termed "immune semaphorins". It is known that Sema4A has three functional receptors, namely Plexin D1, Plexin B1, and Tim-2, whereas Sema4D binds to Plexin B1 and CD72. Recent studies suggest that immune semaphorins play critical roles in many physiological and pathological processes and such. In this review, we summarize the current knowledge on the biology of neuroimmune semaphorins and their corresponding receptors, their distribution in organs and tissues, function in the immune response, and critical regulatory roles in various diseases.

MeSH Terms
Animals Antigens, Differentiation, B-Lymphocyte/immunology Disease Humans Immunity/immunology Nerve Tissue Proteins/chemistry,immunology Neuroimmunomodulation/immunology Receptors, Cell Surface/chemistry,immunology Semaphorins/chemistry,immunology
Chemicals
Antigens, Differentiation, B-Lymphocyte Nerve Tissue Proteins Receptors, Cell Surface Semaphorins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Nkyimbeng-Takwi EusebiusHenry
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Chapoval Svetlana P
References (79)
79 references, click to expand
  1. Mastocytosis: state of the art.
    Pathobiology. 2007;74(2):121-32 PMID: 17587883
  2. Inhibitory receptors, ITIM sequences and phosphatases.
    Curr Opin Immunol. 1997 Jun;9(3):338-43 PMID: 9203414
  3. Involvement of Sema4A in the progression of experimental autoimmune myocarditis.
    FEBS Lett. 2008 Nov 26;582(28):3935-40 PMID: 18977352
  4. Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family.
    Immunity. 2007 Mar;26(3):299-310 PMID: 17363299
  5. Positive signaling through CD72 induces mitogen-activated protein kinase activation and synergizes with B cell receptor signals to induce X-linked immunodeficiency B cell proliferation.
    J Immunol. 2001 Aug 1;167(3):1263-73 PMID: 11466342
  6. Tim-2 regulates T helper type 2 responses and autoimmunity.
    J Exp Med. 2005 Aug 1;202(3):437-44 PMID: 16043519
  7. Endogenous CD100 promotes glomerular injury and macrophage recruitment in experimental crescentic glomerulonephritis.
    Immunology. 2009 Sep;128(1):114-22 PMID: 19689741
  8. CD72 negatively regulates signaling through the antigen receptor of B cells.
    J Immunol. 2000 Feb 1;164(3):1223-9 PMID: 10640734
  9. Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis.
    J Immunol. 2001 Apr 1;166(7):4341-7 PMID: 11254687
  10. Plexin D1 is ubiquitously expressed on tumor vessels and tumor cells in solid malignancies.
    BMC Cancer. 2009 Aug 25;9:297 PMID: 19703316
  11. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling.
    Immunity. 2000 Nov;13(5):621-31 PMID: 11114375
  12. Controlling the immune system through semaphorins.
    Sci STKE. 2002 Apr 16;2002(128):re4 PMID: 11972358
  13. Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells.
    J Immunol. 2002 Aug 1;169(3):1175-81 PMID: 12133937
  14. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury.
    Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1621-6 PMID: 17244710
  15. Activation signals are delivered through two distinct epitopes of CD100, a unique 150 kDa human lymphocyte surface structure previously defined by BB18 mAb.
    Int Immunol. 1995 Jan;7(1):1-8 PMID: 7718506
  16. Mast cell and immune inhibitory receptors.
    Cell Mol Immunol. 2004 Dec;1(6):408-15 PMID: 16293209
  17. Identification of a novel transmembrane semaphorin expressed on lymphocytes.
    J Biol Chem. 1996 Dec 27;271(52):33376-81 PMID: 8969198
  18. Increased surface expression of a newly identified 150-kDa dimer early after human T lymphocyte activation.
    J Immunol. 1992 Jan 15;148(2):318-23 PMID: 1530858
  19. CD100 enhances dendritic cell and CD4+ cell activation leading to pathogenetic humoral responses and immune complex glomerulonephritis.
    J Immunol. 2006 Sep 1;177(5):3406-12 PMID: 16920982
  20. New roles for TIM family members in immune regulation.
    Nat Rev Immunol. 2008 Aug;8(8):577-80 PMID: 18617884
  21. CD100 is a leukocyte semaphorin.
    Cell Mol Life Sci. 1998 Nov;54(11):1265-76 PMID: 9849618
  22. The transmembrane Semaphorin Sema I is required in Drosophila for embryonic motor and CNS axon guidance.
    Neuron. 1998 Feb;20(2):207-20 PMID: 9491983
  23. Cutting edge: inhibition of T cell activation by TIM-2.
    J Immunol. 2006 Oct 15;177(8):4966-70 PMID: 17015678
  24. CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes.
    Blood. 2003 Mar 1;101(5):1962-9 PMID: 12406905
  25. The semaphorin 4D receptor controls invasive growth by coupling with Met.
    Nat Cell Biol. 2002 Sep;4(9):720-4 PMID: 12198496
  26. Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis.
    Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9017-22 PMID: 16754882
  27. Structure determination of human semaphorin 4D as an example of the use of MAD in non-optimal cases.
    Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):108-15 PMID: 16369100
  28. Biochemical identity of the mouse Ly-19.2 and Ly-32.2 alloantigens with the B cell differentiation antigen Lyb-2/CD72.
    J Immunol. 1993 Nov 1;151(9):4764-72 PMID: 8409435
  29. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages.
    Nat Med. 2003 Feb;9(2):191-7 PMID: 12539042
  30. Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis.
    BMC Dev Biol. 2007 May 22;7:55 PMID: 17519029
  31. BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking.
    Eur J Immunol. 2000 May;30(5):1326-30 PMID: 10820378
  32. Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns.
    Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4120-5 PMID: 8633026
  33. Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension.
    Neuron. 1995 May;14(5):941-8 PMID: 7748561
  34. The semaphorins.
    Genome Biol. 2006;7(3):211 PMID: 16584533
  35. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.
    Cell. 1999 Oct 1;99(1):71-80 PMID: 10520995
  36. Impairment of B cell receptor-mediated Ca2+ influx, activation of mitogen-activated protein kinases and growth inhibition in CD72-deficient BAL-17 cells.
    Int Immunol. 2004 Jul;16(7):971-82 PMID: 15148289
  37. TIM family proteins and autoimmunity.
    Autoimmunity. 2007 Sep;40(6):405-8 PMID: 17729033
  38. Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses.
    Int Immunol. 2003 Aug;15(8):1027-34 PMID: 12882840
  39. A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members.
    Neuron. 1997 Sep;19(3):531-7 PMID: 9331346
  40. The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion.
    J Neurosci. 2003 Oct 8;23(27):9229-39 PMID: 14534257
  41. The leukocyte semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin's lymphomas.
    Am J Pathol. 1998 Jul;153(1):255-62 PMID: 9665486
  42. The sema domain.
    Curr Opin Struct Biol. 2004 Dec;14(6):669-78 PMID: 15582390
  43. Neovascularization in human atherosclerosis.
    Circulation. 2006 May 9;113(18):2245-52 PMID: 16684874
  44. The human semaphorin-like leukocyte cell surface molecule CD100 associates with a serine kinase activity.
    J Biol Chem. 1997 Sep 19;272(38):23515-20 PMID: 9295286
  45. Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation.
    J Exp Med. 2003 Mar 17;197(6):751-62 PMID: 12629067
  46. MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D.
    J Biol Chem. 2007 Mar 2;282(9):6899-905 PMID: 17204469
  47. Identification of antigenic epitopes on human allergens: studies with HLA transgenic mice.
    Environ Health Perspect. 2003 Feb;111(2):245-50 PMID: 12573914
  48. PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis.
    Dev Dyn. 2002 Nov;225(3):336-43 PMID: 12412018
  49. Functional regulation of semaphorin receptors by proprotein convertases.
    J Biol Chem. 2003 Mar 21;278(12):10094-101 PMID: 12533544
  50. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.
    Science. 2005 Jan 14;307(5707):265-8 PMID: 15550623
  51. Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation.
    Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11780-5 PMID: 8876214
  52. Immune semaphorins: a new area of semaphorin research.
    J Cell Sci. 2003 Sep 1;116(Pt 17):3463-70 PMID: 12893810
  53. Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs.
    Development. 1995 Dec;121(12):4309-18 PMID: 8575331
  54. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D.
    Nat Struct Biol. 2003 Oct;10(10):843-8 PMID: 12958590
  55. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice.
    Immunity. 2005 Mar;22(3):305-16 PMID: 15780988
  56. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2.
    Nature. 2002 Oct 10;419(6907):629-33 PMID: 12374982
  57. Plexina1 autoinhibition by the plexin sema domain.
    Neuron. 2001 Feb;29(2):429-39 PMID: 11239433
  58. Vascular endothelial growth factor enhances atherosclerotic plaque progression.
    Nat Med. 2001 Apr;7(4):425-9 PMID: 11283668
  59. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis.
    J Exp Med. 2005 Oct 3;202(7):955-65 PMID: 16203866
  60. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis.
    J Immunol. 2010 Feb 1;184(3):1499-506 PMID: 20038643
  61. Deletion of Sema4D gene reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.
    Int J Mol Med. 2010 Jul;26(1):39-44 PMID: 20514420
  62. CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion.
    J Immunol. 1996 Dec 15;157(12):5262-8 PMID: 8955171
  63. CD72, a negative regulator of B-cell responsiveness.
    Immunol Rev. 2000 Aug;176:75-85 PMID: 11043769
  64. Sema4A induces cell morphological changes through B-type plexin-mediated signaling.
    Int J Mol Med. 2010 Feb;25(2):225-30 PMID: 20043131
  65. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice.
    Immunity. 2000 Nov;13(5):633-42 PMID: 11114376
  66. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages.
    J Exp Med. 2008 Jul 7;205(7):1673-85 PMID: 18559453
  67. The CD100-CD72 interaction: a novel mechanism of immune regulation.
    Trends Immunol. 2001 Dec;22(12):670-6 PMID: 11738997
  68. Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B.
    Cancer Res. 2004 Aug 1;64(15):5212-24 PMID: 15289326
  69. Soluble CD100 functions on human monocytes and immature dendritic cells require plexin C1 and plexin B1, respectively.
    Int Immunol. 2005 Apr;17(4):439-47 PMID: 15746246
  70. Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration.
    J Immunol. 2001 Apr 1;166(7):4348-54 PMID: 11254688
  71. Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1.
    EMBO J. 2007 Mar 7;26(5):1373-84 PMID: 17318185
  72. Semaphorins and their receptors in immune cell interactions.
    Nat Immunol. 2008 Jan;9(1):17-23 PMID: 18087252
  73. Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosis.
    Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1039-45 PMID: 19390055
  74. CD72 negatively regulates KIT-mediated responses in human mast cells.
    J Immunol. 2010 Mar 1;184(5):2468-75 PMID: 20100931
  75. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.
    Nature. 1996 Oct 10;383(6600):525-8 PMID: 8849723
  76. Myocarditis.
    Prog Cardiovasc Dis. 2010 Jan-Feb;52(4):274-88 PMID: 20109598
  77. Structure and function of the intracellular region of the plexin-b1 transmembrane receptor.
    J Biol Chem. 2009 Dec 18;284(51):35962-72 PMID: 19843518
  78. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor.
    Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):674-8 PMID: 8570614
  79. Sema4D induces angiogenesis through Met recruitment by Plexin B1.
    Blood. 2005 Jun 1;105(11):4321-9 PMID: 15632204
Article Info
Journal
Immunologic research
Abbr.
Immunol Res
ISSN
1559-0755
DOI
10.1007/s12026-010-8201-y
Published
2011-05-00
Pages
10-21
Language
English
Region
United States
NLM ID
8611087
PMCID
PMC3366695
Subset
IM
Grants
NIAID NIH HHS · R21 AI076736 · United States
NIAID NIH HHS · R21AI076736 · United States
External Links
PubMed source DOI: 10.1007/s12026-010-8201-y PMC Full Text View journal details
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