In the last few years it has become clear that in cells of the immune system, specialized microdomains present in the plasma membrane, called lipid rafts, have been found to play a central role in regulating signalling by immune receptors. Recent studies have looked at whether lipid rafts may be connected to the abnormalities in signalling seen in T lymphocytes isolated from patients with systemic lupus erythematosus (SLE). These early findings show that in SLE T cells, the expression and protein composition of lipid rafts is different when compared with normal T cells. These results also demonstrate changes in the function and localization of critical signalling molecules such as the LCK tyrosine kinase and the CD45 tyrosine phosphatase.
Morrow J , Nelson L , Watts R , Isenberg D.Systemic lupus erythematosus. In Morrow J , Nelson L , Watts R , Isenberg D eds. Autoimmune rheumatic disease, second edition. Oxford, UK: Oxford University Press , 1999: 56-103.
2.
Dayal AK , Kammer GM.The T cell enigma in lupus . Arthritis Rheum1996; 39: 23-33 .
3.
Tsokos GC , Liossis S-NC.Immune cell signalling defects in lupus: activation, anergy and death . Immunol Today1999; 20: 199-124 .
4.
Baechler EC , Batliwalla FM , Karypis Get al.Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus . Proc Natl Acad Sci USA2003; 100: 2610-2615 .
5.
Bennett L , Palucka AK , Arce Eet al.Interferon and granulopoiesis signatures in systemic lupus erythematosus blood . J Exp Med2003; 197: 711-723 .
6.
Ohashi PS.T cell signalling and autoimmunity: molecular mechanisms of disease . Nat Rev Immunol2002; 2: 427-438 .
7.
Pascual V , Banchereau J , Palucka AK.The central role of dendritic cells and interferon-alpha in SLE . Curr Opin Rheum2003; 15: 548-556 .
8.
White S , Rosen A.Apoptosis in systemic lupus erythematosus . Curr Opin Rheum2003; 15: 557-562 .
9.
Salomon B , Bluestone JA.Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation . Annu Rev Immunol2001; 19: 225-252 .
10.
Tsokos GC , Nambiar MP , Tenbrock K , Juang Y-T.Rewiring the T-cell: signalling defects and novel prospects for the treatment of SLE . Trends Immunol2003; 24: 259-263 .
11.
Kammer GM , Perl A , Richardson BC , Tsokos GC.Abnormal T cell signal transduction in systemic lupus erythematosus . Arthritis Rheum2002; 46: 1139-1154 .
12.
Jury EC , Kabouridis PS , Abba A , Mageed RA , Isenberg DA.Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosus . Arthritis Rheum2003; 48: 1343-1354 .
13.
Jury EC , Kabouridis PS , F Flores-Borja , Mageed RA , Isenberg DA.Altered lipid raft-associated signalling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus . J Clin Invest2004; 113: 1176-1187 .
14.
Nambiar MP , Enyedy EJ , Fisher CUet al.Abnormal expression of various molecular forms and distruption of T cell receptor ζ chain in patients with systemic lupus erythematosus . Arthritis Rheum2002; 46: 163-174 .
15.
Mustelin T , Taskén K.Positive and negative regulation of T-cell activation through kinases and phosphatases . Biochem J2003; 371: 15-27 .
16.
Davis SJ , Van der Merwe PA.The structure and ligand interactions of CD2: implications for T cell function . Immunol Today1996; 17: 177-187 .
17.
Zhang W , Sloan-Lancaster J , Kitchen J , Trible RP , Samelson LE.LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation . Cell1998; 92: 83-92 .
18.
Zhang W , Samelson LE.The role of membrane-associated adaptors in T cell receptor signalling . Cell2000; 12: 35-41 .
19.
Simons K , Toomre D.Lipid rafts and signal transduction . Nature Rev2000; 1: 31-39 .
20.
Janes PW , Ley SC , Magee AI , Kabouridis PS.The role of lipid rafts in T cell antigen receptor (TCR) signalling . Semin Immunol2000; 12: 23-34 .
21.
Singer AL , Koretzky GA.Control of T cell function by positive and negative regulators . Science2002; 296: 1639-1640 .
22.
Simons K , Ikonen E.Functional rafts in cell membranes . Nature1997; 387: 569-572 .
23.
Brown DA , London E.Functions of lipid rafts in biological membranes . Annu Rev Cell Dev Biol1998; 14: 111-136 .
24.
Dykstra M , Cherukuri A , Sohn HW , Tzeng S-J , Pierce SK.Location is everything: Lipid rafts and immune cell signalling . Annu Rev Immunol2003; 21: 457-481 .
25.
Viola A , Schroeder S , Sakakibara Y , Lanzavecchia A.T lymphocyte costimulation mediated by reorganisation of membrane microdomains . Science1999; 283: 680-682 .
26.
Tuosto L , Parolini I , Schroder S , Sariacomo M , Lanzavecchia A , Viola A.Organisation of plasma membrane functional rafts upon T cell activation . Eur J Immunol2001; 31: 345-349 .
27.
Tomlinson MG , Lin J , Weiss A.Lymphocytes with a complex: adapter proteins in antigen receptor signalling . Immunol Today2000; 21: 584-591 .
28.
Brdicka T , Pavlistova D , Leo Aet al.Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation . J Exp Med2000; 191: 1591-1604 .
29.
Xavier R , Brennan T , Li Q , McCormack C , Seed B.Membrane compartmentation is required for efficient T cell activation . Immunity1998; 8: 723-732 .
30.
Giurisato E , McIntosh DP , Tassi M , Gamberucci A , Benedetti A.T cell receptor can be recruited to a subset of plasma membrane rafts, independently of cell signaling and attendantly to raft clustering . J Biol Chem2003; 278: 6771-6778 .
31.
Freiberg BA , Kupfer H , Maslanik JD , Kappler J , Zaller DM , Kupfer A.Staging and resetting T cell activation in SMACs . Nature Immunol2002; 3: 911-917 .
32.
Rodgers W , Rose JK.Exclusion of CD45 inhibits activity of p56lck associated with glycolipid-enriched membrane domains . J Cell Biol1996; 135: 1515-1523 .
33.
Burack WR , Lee KH , Holdorf AD , Dustin ML , Shaw AS.Quantitative imaging of raft accumulation in the immunological synapse . J Immunol2002; 169: 2837-2841 .
34.
Acuto O , Cantrell D.T cell activation and the cytoskeleton . Annu Rev Immunol2000; 18: 165-184 .
35.
Rodgers W and Zavzavadjian J.Glycolipid-enriched membrane domains are assembled into membrane patches by associating with the actin cytoskeleton . Exp Cell Res2001; 267: 173-183 .
36.
Jordan S , Rodgers W.T cell glycolipid-enriched membrane domains are constitutively assembled as membrane patches that translocate to immune synapses . J Immunol2003; 171: 78-87 .
37.
Martin M , Schneider H , Azouz A , Rudd CE.Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function . J Exp Med2001; 194: 1675-1681 .
38.
Vratsanos GS , Jung S , Park YM , Craft J.CD4(+) T cells from lupus-prone mice are hyperresponsive to T cell receptor engagement with low and high affinity peptide antigens: a model to explain spontaneous T cell activation in lupus . J Exp Med2001; 193: 329-337 .
39.
Schade AE , Levine AD.Lipid raft heterogeneity in human peripheral blood T lymphoblasts: A mechanism for regulating the initiation of TCR signal transduction . J Immunol2002; 168: 2233-2239 .
40.
Drevot P , Langlet C , Guo XJet al.TCR signal initiation machinery is pre-assembled and activated in a subset of membrane rafts . EMBO J2002; 21: 1899-1908 .
41.
Pike LJ.Lipid rafts: heterogeneity on the high seas . Biochem J2004; 378: 281-292 .
42.
Gomez-Mouton C , Abad JL , Mira Eet al.Segregation of leading edge and uropod components into specific lipid rafts during T cell polarization . Proc Natl Acad Sci USA2001; 98: 9642-9647 .
43.
Kammer GM.Impaired T cell capping and receptor regeneration in active systemic lupus erythematosus: evidence for a disorder intrinsic to the T lymphocyte . J Clin Invest1983; 72: 1686-1697 .
44.
Matache C , Stefanescu M , Onu Aet al.Tyrosine phosphorylation in peripheral lymphocytes from patients with systemic lupus erythematosus . Autoimmunity1996; 24: 217-228 .
45.
Matache C , Stefanescu M , Onu Aet al.P56lck activity and expression in peripheral blood lymphocytes from patients with systemic lupus erythematosus . Autoimmunity1999; 29: 111-120 .
46.
Blasini AM , Alonzo E , Chacon R , Riera R , Stekman IL , Rodriguez MA.Abnormal pattern of tyrosine phosphorylation in unstimulated peripheral blood T lymphocytes from patients with systemic lupus erythematosus . Lupus1998; 7: 515-523 .
47.
Blasini AM , Brundula V , Paris Met al.Protein tyrosine kinase activity in T lymphocytes from patients with systemic lupus erythematosus . J Autoimmunity1998; 11: 387-393 .
48.
Molina TJ , Kishihara K , Siderovski DPet al.Profound block in thymocyte development in mice lacking p56lck . Nature1992; 357: 161-164 .
49.
Kabouridis PS , Magee AI , Ley SC.S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes . EMBO J1997; 16: 4983-4998 .
50.
Straus D , Weiss A.Genetic evidence for the involvement of the lck tryrosine kinase in signal transduction through the T cell antigen receptor . Cell1992; 70: 585-593 .
51.
Ardouin L , Boyer C , Gillet Aet al.Crippling of CD3-ζ ITAMs does not impair T cell receptor signalling . Immunity1999; 10: 409-420 .
52.
Enyedy EJ , Nambiar MP , Liossis S-NC , Dennis G , Kammer GM , Tsokos GC.Fcε receptor type I γ chain in T cells of patients with systemic lupus erythematosus . Arthritis Rheum2001; 44: 1114-1121 .
53.
Holdorf AD , Green JM , Levin SDet al.Proline residues in CD28 and Src homology (SH)3 domain of Lck are required for T cell costimulation . J Exp Med1999; 190: 375-384 .
54.
Acuto O , Michel F.CD28-mediated co-stimulation: a quantitative support for TCR signalling . Nature Rev Immunol2003; 3: 939-951 .
55.
Seddon B , Legname G , Tomlinson P , Zamoyska R.Long-term survival but impaired homeoststic proliferation of naive T cells in the absence of p56lck . Science2000; 290: 127-131 .
56.
Trowbridge PA , Levin SD.Lck plays a critical role in Ca2+ moblization and CD28 costimulation in mature primary T cells . Eur J Immunol2001; 31: 3567-3579 .
57.
Nervi S , Atlan-Gepner C , Kahn-Perles Bet al.Specific deficiency of p56lck expression in T lymphocytes from type I diabetic patients . J Immunol2000; 165: 5874-5883 .
58.
Romagnoli P , Strahan D , Pelosi M , Cantagrel A , van Meerwijk JPM.A potential role for protein tyrosine kinase p56lck in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness . Int Immunol2001; 13: 305-312 .
59.
Horwitz DA , Stohl W , Gray JD.T lymphocytes, natural killer cells and immune regulation. In Wallace DJ , Hann BH eds. Dubois lupus erythematosus, sixth edition. Philadelphia, USA: Lippincott, Williams and Wilkins , 2002: 157-185.
60.
Ben-Neriah Y.Regulatory functions of ubiquitination in the immune system . Nature Immunol2002; 3: 20-26 .
61.
Hermiston ML , Xu Z , Majeti R , Weiss A.Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases . J Clin Invest2002; 109: 9-14 .
62.
Penninger JM , Irie-Sasaki J , Sasaki T , Oliveira-dos-Santos AJ.CD45: new jobs for an old acquaintance . Nature Immunol2001; 2: 389-396 .
63.
Rao N , Miyake S , Reddi ALet al.Negative regulation of Lck by Cbl ubiquitin ligase . Proc Natl Acad Sci USA2002; 99: 3794-3799 .
64.
Hawash IY , Kesavan KP , Magee AI , Geahlen RL , Harrison ML.The Lck SH3 domain negatively regulates localisation to lipid rafts through an interation with c-Cbl . J Biol Chem2002; 277: 5683-5691 .
65.
Leitenberg D , Balamuth F , Bottomly K.Changes in the T cell receptor macromolecular signalling complex and membrane microdomains during T cell development and activation . Semin Immunol2001; 13: 129-138 .
Furukawa T , Itoh M , Krueger NX , Streuli M , Saito H.Specific interaction of the CD45-protein tyrosine phosphorylated CD3 ζ chain . Proc Natl Acad Sci USA1994; 25: 942-946 .
68.
Hermiston ML , Xu Z , Weiss A.CD45: a critical regulator of signalling thresholds in immune cells . Annu Rev Immunol2003; 21: 107-137 .
69.
Janes PW , Ley SC , Magee AI.Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor . J Cell Biol1999; 174: 447-461 .
70.
Edmonds SD , Ostergaard HL.Dynamic association of CD45 with detergent-insoluble microdomains in T lymphocytes . J Immunol2002; 169: 5036-5042 .
71.
Irles C , Symons A , Michel F , Bakker TR , van der Merwe PA , Acuto O.CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling . Nat Immunol2003; 4: 189-197 .
72.
Vassilopoulos D , Kovacs B , Tsokos GC.TCR/CD3 complex-mediated signal transduction pathway in T cell lines from patients with systemic lupus erythematosus . J Immunol1995; 155: 2269-2281 .
73.
Dar O , Salamam MR , Seifert MH , Isenberg DA.Spontaneous antibody secreting cells against DNA and common environmental antigens in systemic lupus erythematosus . J Autoimmunity1990; 3: 523-530 .
74.
Takeuchi T , Pang M , Amano J , Koide J , Abe T.Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE) . Clin Exp Immunol1997; 109: 20-26 .
75.
Xu Z , Weiss A.Negative regulation of CD45 by differential homodimerisation of the alternatively spliced isoforms . Nature Immunol2002; 3: 764-771 .
76.
Majeti R , Xu Z , Parslow TGet al.An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity . Cell2000; 103: 1059-1070 .
77.
Dornan S , Sebestyen Z , Gamble Jet al.Differential association of CD45 isoforms with CD4 and CD8 regulates the actions of specific pools of p56lck tyrosine kinase in T cell antigen receptor signal transduction . J Biol Chem2002; 277: 1912-1918 .
78.
Ishii T , Ohnuma K , Murakami Aet al.CD26-mediated signalling for T cell activation occurs in lipid rafts through its association with CD45RO . PNAS2001; 98: 12138-12143 .
79.
Salgado FJ , Lojo J , Alonso-Lebrero JLet al.A role for IL-12 in the regulation of T cell plasma membrane compartmentation . J Biol Chem2003; 278: 24849-24857 .
80.
Kammer GM , Khan IU , Malemud CJ.Deficient type I protein kinase A isoenzyme activity in systemic lupus erythematosus T lymphocytes . J Clin Invest1994; 94: 422-430 .
81.
Torgersen KM , Vang T , Abrahamsen Het al.Release from tonic inhibition of T cell activation through transient displacement of C-terminal Src kinase (CSK) from lipid rafts . J Biol Chem2001; 276: 29313-29318 .
82.
Aandahl EM , Moretto WJ , Haslett PAet al.Inhibition of antigen-specific T cell proliferation and cytokine production by protein kinase A type I . J Immunol2002; 169: 802-808 .
83.
Vang T , Sundvold V , Levy FOet al.Activation of the COOH-terminal Src kinase (CSK) by cAMP-dependent protein kinase inhibits signalling through the T cell receptor . J Exp Med2001; 193: 497-507 .
84.
Krawczyk C , Penninger JM.Molecular controls of antigen receptor clustering and autoimmunity . Trends Cell Biol2001; 11: 212-220 .
85.
Liu Y-C , Gu H.Cbl and Cbl-b in T-cell regulation . Trends Immunol2002; 23: 140-143 .
86.
Murphy MA , Schnall RG , Venter DJet al.Tissue hyperplasia and enhanced T cell signalling via ZAP-70 in c-Cbl deficient mice . Mol Cell Biol1998; 18: 4872-4882 .
87.
Naramura M , Kole HK , Hu RJ , Gu H.Altered thymic positive selection and intracellular signals in cbl-deficient mice . PNAS1998; 95: 15547-15552 .
88.
Rudd CE , Schneider H.Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling . Nature Rev Immunol2003; 3: 544-556 .
89.
Krawczyk C , Bachmaier K , Sasaki Tet al.Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells . Immunity2000; 13: 463-473 .
90.
Yi Y , McNerney M , Datta SK.Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells . J Immunol2000; 165: 6627-6634 .
91.
Blanco P , Palucka AK , Gill M , Pascual V , Banchereau J.Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus . Science2001; 294: 1540-1543 .
92.
Hooks JJ , Moutsopoulos HM , Geis SA , Stahl NI , Decker JL , Notkins AL.Immune interferon in the circulation of patients with autoimmune disease . N Engl J Med1979; 301: 5-8 .
