The role of cholesterol in TCR signalling in autoimmune diseases
Main Article Content
Abstract
Cholesterol is an important structural and functional component of the plasma membrane. In this review, we focus on T cells and the role of cholesterol in T cell antigen receptor (TCR) signalling, which contributes to autoimmune diseases. Cholesterol binding to the TCR leads to an increased formation of TCR nanoclusters, increasing the avidity of T cells towards the antigen and enabling TCR cooperativity, thus increasing the sensitivity of the T cell. Further, cholesterol is important in the formation of certain lipid nanodomains, called lipid rafts that concentrate signalling molecules and thus also promote TCR signalling. T cell and lipid dysregulation play a key role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Typically, in SLE, hyper-responsive and exaggerated TCR signalling occurs, partially caused by cholesterol accumulation in the plasma membrane. This might lead to enhanced TCR nanoclustering and lipid raft formation. Thus, targeting lipid metabolism in T cells.
Article Details
How to Cite
PATHAN-CHHATBAR, Salma et al.
The role of cholesterol in TCR signalling in autoimmune diseases.
Medical Research Archives, [S.l.], v. 9, n. 2, feb. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2284>. Date accessed: 24 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i2.2284.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol. 2020;21:605-614
2. Shlomchik MJ, Craft JE & Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2011;1:147-153
3. Hartl FA, et al. Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nat Immunol. 2020;21:902-913.
4. Reth M. Antigen receptor tail clue. Nature. 1989;338:383-384
5. Weiss A. The right team at the right time to go for a home run: tyrosine kinase activation by the TCR. Nat Immunol. 2010; 11:101-104
6. Gil D, Schamel WW, Montoya M, Sanchez-Madrid F & Alarcon B. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002;109: 901-912
7. Acuto O, Di Bartolo V & Michel F. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nat Rev Immunol. 2008;8:699-712
8. Courtney AH, Lo WL & Weiss A. TCR Signaling: Mechanisms of Initiation and Propagation. Trends Biochem Sci. 2018;43:108-123
9. Samelson LE. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Ann Rev Immunol. 2001;20:371-394
10. Schamel WW, Alarcon B & Minguet S. The TCR is an allosterically regulated macromolecular machinery changing its conformation while working. Immunological reviews. 2019;291:8-25
11. Schamel WW, Alarcon B, Hofer T & Minguet S. The Allostery Model of TCR Regulation. J Immunol. 2017;198:47-52
12. Minguet S, Swamy M, Alarcon B, Luescher IF & Schamel WW. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity. 2007;26:43-54
13. Gil D, Schrum AG, Alarcon B & Palmer E. T cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J. Exp. Med. 2005;201:517-522
14. Lee MS, et al. A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3zetazeta. Immunity. 2015;43:227-239
15. Swamy M, et al. A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. Immunity. 2016;44:1091-1101
16. Molnar E, et al. Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J Biol Chem. 2012;287:42664-42674
17. Schamel WW & Alarcon B. Organization of the resting TCR in nanoscale oligomers. Immunol Rev. 2013;251:13-20
18. Schamel WW, et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med. 2005;202:493-503
19. Lillemeier BF, et al. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat Immunol. 2010;11:90-96
20. Kumar R, et al. Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes. Immunity. 2011;35:375-387
21. Kersh EN, et al. TCR signal transduction in antigen-specific memory CD8 T cells. J Immunol. 2003;170:5455-5463
22. Tani-ichi S, et al. Structure and function of lipid rafts in human activated T cells. Int Immunol. 2005;17:749-758
23. Kaech SM, Hemby S, Kersh E & Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell. 2002;111:837-851
24. Fahmy TM, Bieler JG, Edidin M & Schneck JP. Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Immunity. 2011;14:135-143
25. Drake III DR & Braciale TJ. Cutting edge: lipid raft integrity affects the efficiency of MHC class I tetramer binding and cell surface TCR arrangement on CD8+ T cells. J Immunol. 2001;166:7009-7013
26. Martinez-Martin N, et al. Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3epsilon. Sci Signal. 2009;2:ra43
27. Martin-Blanco N, et al. A window of opportunity for cooperativity in the T Cell Receptor. Nat Com. 2018;9:2618
28. Simons K & Ikonen E. Functional rafts in cell membranes. Nature.1997;387:569-572
29. Montixi C, et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 1998;17:5334-5348
30. Xavier R, Brennan T, Li Q, McCormack C & Seed B. Membrane compartmentation is required for efficient T cell activation. Immunity. 1998;8:723-732
31. Simons K & Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31-39
32. Levental I, Grzybek M, Simons K. Raft domains of variable properties and compositions in plasma membrane vesicles. Proc Natl Acad Sci USA. 2011;108:11411- 11416
33. Eggeling C, et al. Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature. 2009;457:1159-1162
34. Mueller V, et al. STED nanoscopy reveals molecular details of cholesterol- and cytoskeleton-modulated lipid interactions in living cells. Biophys J. 2011;101:1651-1660
35. Sharma P, et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell. 2004;116:577-589
36. Veiga MP, Arrondo JL, Goni FM, Alonso A & Marsh D. Interaction of cholesterol with sphingomyelin in mixed membranes containing phosphatidylcholine, studied by spin-label ESR and IR spectroscopies. A possible stabilization of gel-phase sphingolipid domains by cholesterol. Biochemistry. 2011;40:2614-2622
37. Bjorkbom A, et al. N- and O-methylation of sphingomyelin markedly affects its membrane properties and interactions with cholesterol. Biochim Biophys Acta. 2011;1808:1179-1186
38. Demel RA, Jansen JW, van Dijck PW & van Deenen LL. The preferential interaction of cholesterol with different classes of phospholipids. Biochim Biophys Acta.1977;465:1-10
39. Endapally S, et al. Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes. Cell. 2019;176:1040-1053
40. Chyu KY, et al. Cholesterol lowering modulates T cell function in vivo and in vitro. PLoS One. 2014;9:e92095
41. Moulton VR & Tsokos GC. T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest. 2015;125:2220-2227
42. Rother N & van der Vlag J. Disturbed T Cell Signaling and Altered Th17 and Regulatory T Cell Subsets in the Pathogenesis of Systemic Lupus Erythematosus. Front Immunol. 2015;6:610
43. Kammer GM, Perl A, Richardson BC & Tsokos GC. Abnormal T cell signal transduction in systemic lupus erythematosus. Arthritis Rheum. 2001;46:1139-1154
44. Kidani Y & Bensinger SJ. Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus. J Clin Invest. 2014;124:482-485
45. Enyedy EJ, et al. Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2011;44:1114-1121
46. Krishnan S, Warke VG, Nambiar MP, Tsokos GC & Farber DL. The FcR gamma subunit and Syk kinase replace the CD3 zeta-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J Immunol. 2003;170:4189-4195
47. Roman MJ, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. New Engl J Med. 2003;349:2399-2406
48. Vukelic M, Kono M & Tsokos GC. T cell Metabolism in Lupus. Immunometabolism. 2020;2:e200009
49. Yang Z, Matteson EL, Goronzy JJ & Weyand CM. T-cell metabolism in autoimmune disease. Arthritis Res Ther. 2015;17:29
50. Jury EC, Kabouridis PS, Flores-Borja F, Mageed RA & Isenberg DA. Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J Clin Invest. 2004;113:1176-1187
51. McDonald G, et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J Clin Invest. 2014;124:712-724
52. Krishnan S, et al. Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J Immunol. 2004;172:7821-7831
53. Jury EC, Isenberg DA, Mauri C & Ehrenstein MR. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol. 2006;177:7416-7422
54. Deng GM & Tsokos GC. Cholera Toxin B Accelerates Disease Progression in Lupus-Prone Mice by Promoting Lipid Raft Aggregation. J Immunol. 2008;181:4019-4026
2. Shlomchik MJ, Craft JE & Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2011;1:147-153
3. Hartl FA, et al. Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nat Immunol. 2020;21:902-913.
4. Reth M. Antigen receptor tail clue. Nature. 1989;338:383-384
5. Weiss A. The right team at the right time to go for a home run: tyrosine kinase activation by the TCR. Nat Immunol. 2010; 11:101-104
6. Gil D, Schamel WW, Montoya M, Sanchez-Madrid F & Alarcon B. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002;109: 901-912
7. Acuto O, Di Bartolo V & Michel F. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nat Rev Immunol. 2008;8:699-712
8. Courtney AH, Lo WL & Weiss A. TCR Signaling: Mechanisms of Initiation and Propagation. Trends Biochem Sci. 2018;43:108-123
9. Samelson LE. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Ann Rev Immunol. 2001;20:371-394
10. Schamel WW, Alarcon B & Minguet S. The TCR is an allosterically regulated macromolecular machinery changing its conformation while working. Immunological reviews. 2019;291:8-25
11. Schamel WW, Alarcon B, Hofer T & Minguet S. The Allostery Model of TCR Regulation. J Immunol. 2017;198:47-52
12. Minguet S, Swamy M, Alarcon B, Luescher IF & Schamel WW. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity. 2007;26:43-54
13. Gil D, Schrum AG, Alarcon B & Palmer E. T cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J. Exp. Med. 2005;201:517-522
14. Lee MS, et al. A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3zetazeta. Immunity. 2015;43:227-239
15. Swamy M, et al. A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. Immunity. 2016;44:1091-1101
16. Molnar E, et al. Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J Biol Chem. 2012;287:42664-42674
17. Schamel WW & Alarcon B. Organization of the resting TCR in nanoscale oligomers. Immunol Rev. 2013;251:13-20
18. Schamel WW, et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med. 2005;202:493-503
19. Lillemeier BF, et al. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat Immunol. 2010;11:90-96
20. Kumar R, et al. Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes. Immunity. 2011;35:375-387
21. Kersh EN, et al. TCR signal transduction in antigen-specific memory CD8 T cells. J Immunol. 2003;170:5455-5463
22. Tani-ichi S, et al. Structure and function of lipid rafts in human activated T cells. Int Immunol. 2005;17:749-758
23. Kaech SM, Hemby S, Kersh E & Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell. 2002;111:837-851
24. Fahmy TM, Bieler JG, Edidin M & Schneck JP. Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Immunity. 2011;14:135-143
25. Drake III DR & Braciale TJ. Cutting edge: lipid raft integrity affects the efficiency of MHC class I tetramer binding and cell surface TCR arrangement on CD8+ T cells. J Immunol. 2001;166:7009-7013
26. Martinez-Martin N, et al. Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3epsilon. Sci Signal. 2009;2:ra43
27. Martin-Blanco N, et al. A window of opportunity for cooperativity in the T Cell Receptor. Nat Com. 2018;9:2618
28. Simons K & Ikonen E. Functional rafts in cell membranes. Nature.1997;387:569-572
29. Montixi C, et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 1998;17:5334-5348
30. Xavier R, Brennan T, Li Q, McCormack C & Seed B. Membrane compartmentation is required for efficient T cell activation. Immunity. 1998;8:723-732
31. Simons K & Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31-39
32. Levental I, Grzybek M, Simons K. Raft domains of variable properties and compositions in plasma membrane vesicles. Proc Natl Acad Sci USA. 2011;108:11411- 11416
33. Eggeling C, et al. Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature. 2009;457:1159-1162
34. Mueller V, et al. STED nanoscopy reveals molecular details of cholesterol- and cytoskeleton-modulated lipid interactions in living cells. Biophys J. 2011;101:1651-1660
35. Sharma P, et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell. 2004;116:577-589
36. Veiga MP, Arrondo JL, Goni FM, Alonso A & Marsh D. Interaction of cholesterol with sphingomyelin in mixed membranes containing phosphatidylcholine, studied by spin-label ESR and IR spectroscopies. A possible stabilization of gel-phase sphingolipid domains by cholesterol. Biochemistry. 2011;40:2614-2622
37. Bjorkbom A, et al. N- and O-methylation of sphingomyelin markedly affects its membrane properties and interactions with cholesterol. Biochim Biophys Acta. 2011;1808:1179-1186
38. Demel RA, Jansen JW, van Dijck PW & van Deenen LL. The preferential interaction of cholesterol with different classes of phospholipids. Biochim Biophys Acta.1977;465:1-10
39. Endapally S, et al. Molecular Discrimination between Two Conformations of Sphingomyelin in Plasma Membranes. Cell. 2019;176:1040-1053
40. Chyu KY, et al. Cholesterol lowering modulates T cell function in vivo and in vitro. PLoS One. 2014;9:e92095
41. Moulton VR & Tsokos GC. T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest. 2015;125:2220-2227
42. Rother N & van der Vlag J. Disturbed T Cell Signaling and Altered Th17 and Regulatory T Cell Subsets in the Pathogenesis of Systemic Lupus Erythematosus. Front Immunol. 2015;6:610
43. Kammer GM, Perl A, Richardson BC & Tsokos GC. Abnormal T cell signal transduction in systemic lupus erythematosus. Arthritis Rheum. 2001;46:1139-1154
44. Kidani Y & Bensinger SJ. Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus. J Clin Invest. 2014;124:482-485
45. Enyedy EJ, et al. Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2011;44:1114-1121
46. Krishnan S, Warke VG, Nambiar MP, Tsokos GC & Farber DL. The FcR gamma subunit and Syk kinase replace the CD3 zeta-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J Immunol. 2003;170:4189-4195
47. Roman MJ, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. New Engl J Med. 2003;349:2399-2406
48. Vukelic M, Kono M & Tsokos GC. T cell Metabolism in Lupus. Immunometabolism. 2020;2:e200009
49. Yang Z, Matteson EL, Goronzy JJ & Weyand CM. T-cell metabolism in autoimmune disease. Arthritis Res Ther. 2015;17:29
50. Jury EC, Kabouridis PS, Flores-Borja F, Mageed RA & Isenberg DA. Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J Clin Invest. 2004;113:1176-1187
51. McDonald G, et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J Clin Invest. 2014;124:712-724
52. Krishnan S, et al. Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J Immunol. 2004;172:7821-7831
53. Jury EC, Isenberg DA, Mauri C & Ehrenstein MR. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol. 2006;177:7416-7422
54. Deng GM & Tsokos GC. Cholera Toxin B Accelerates Disease Progression in Lupus-Prone Mice by Promoting Lipid Raft Aggregation. J Immunol. 2008;181:4019-4026