T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

Journal of Clinical Investigation

Volumn 125, Issue 6, 2015, Pages 2220-2227

  Moulton, Vaishali R ^a   Tsokos, George C ^a  

^a BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIGEN; AUTOANTIBODY; AUTOANTIGEN; INTERLEUKIN 17; INTERLEUKIN 2;

ARTICLE; AUTOIMMUNITY; B LYMPHOCYTE; CELL INFILTRATION; CELLULAR DISTRIBUTION; CYTOKINE PRODUCTION; EPIGENETICS; GENE CONTROL; GENETIC TRANSCRIPTION; HUMAN; HUMORAL IMMUNITY; IMMUNOCOMPETENT CELL; INFLAMMATORY CELL; LYMPHOCYTE FUNCTION; LYMPHOCYTE HOMING; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; SYSTEMIC LUPUS ERYTHEMATOSUS; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; T LYMPHOCYTE SUBPOPULATION; TARGET ORGAN; ANIMAL; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; LUPUS ERYTHEMATOSUS, SYSTEMIC; LYMPHOCYTE ACTIVATION; PATHOLOGY;

ANIMALS; AUTOANTIBODIES; HUMANS; IMMUNE TOLERANCE; IMMUNITY, HUMORAL; LUPUS ERYTHEMATOSUS, SYSTEMIC; LYMPHOCYTE ACTIVATION; T-LYMPHOCYTES;

EID: 84930409363     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI78087     Document Type: Article

References (106)

1. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22): 2110-2121.
2. Moulton VR, Tsokos GC. Abnormalities of T cell signaling in systemic lupus erythematosus. Arthritis Res Ther. 2011;13(2): 207.
3. Krishnan S, Farber DL, Tsokos GC. T cell rewiring in differentiation and disease. J Immunol. 2003;171(7): 3325-3331.
4. Krishnan S, et al. Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells. J Immunol. 2008;181(11): 8145-8152.
5. Nambiar MP, et al. Reconstitution of deficient T cell receptor zeta chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus. Arthritis Rheum. 2003;48(7): 1948-1955.
6. Juang YT, Tenbrock K, Nambiar MP, Gourley MF, Tsokos GC. Defective production of functional 98-kDa form of Elf-1 is responsible for the decreased expression of TCR ?-chain in patients with systemic lupus erythematosus. J Immunol. 2002;169(10): 6048-6055.
7. Moulton VR, Kyttaris VC, Juang YT, Chowdhury B, Tsokos GC. The RNA-stabilizing protein HuR regulates the expression of ? chain of the human T cell receptor-Associated CD3 complex. J Biol Chem. 2008;283(29): 20037-20044.
8. Moulton VR, Tsokos GC. Alternative splicing factor/splicing factor 2 regulates the expression of the ? subunit of the human T cell receptor-Associated CD3 complex. J Biol Chem. 2010;285(17): 12490-12496.
9. Nambiar MP, et al. Abnormal expression of various molecular forms and distribution of T cell receptor ? chain in patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46(1): 163-174.
10. Krishnan S, et al. Increased caspase-3 expression and activity contribute to reduced CD3? expression in systemic lupus erythematosus T cells. J Immunol. 2005;175(5): 3417-3423.
11. Fernandez DR, et al. Activation of mammalian target of rapamycin controls the loss of TCR? in lupus T cells through HRES-1/Rab4- regulated lysosomal degradation. J Immunol. 2009;182(4): 2063-2073.
12. Deng GM, Beltran J, Chen C, Terhorst C, Tsokos GC. T cell CD3? deficiency enables multiorgan tissue inflammation. J Immunol. 2013;191(7): 3563-3567.
13. Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol. 2013;9(11): 674-686.
14. Fernandez D, Bonilla E, Mirza N, Niland B, Perl A. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(9): 2983-2988.
15. Peairs A, et al. Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/ lpr mouse mesangial cells. Cell Mol Immunol. 2010;7(2): 123-132.
16. Lai ZW, et al. N-Acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, doubleblind, placebo-controlled trial. Arthritis Rheum. 2012;64(9): 2937-2946.
17. 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(12): 7821-7831.
18. Deng GM, Tsokos GC. Cholera toxin B accelerates disease progression in lupus-prone mice by promoting lipid raft aggregation. J Immunol. 2008;181(6): 4019-4026.
19. 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(10): 7416-7422.
20. McDonald G, et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J Clin Invest. 2014;124(2): 712-724.
21. Sinicato NA, da Silva Cardoso PA, Appenzeller S. Risk factors in cardiovascular disease in systemic lupus erythematosus. Curr Cardiol Rev. 2013;9(1): 15-19.
22. Deng GM, Tsokos GC. Cholera toxin B accelerates disease progression in lupus-prone mice by promoting lipid raft aggregation. J Immunol. 2008;181(6): 4019-4026.
23. Crispin JC, et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008;181(12): 8761-8766.
24. Crispin JC, et al. Expression of CD44 variant isoforms CD44v3 and CD44v6 is increased on T cells from patients with systemic lupus erythematosus and is correlated with disease activity. Arthritis Rheum. 2010;62(5): 1431-1437.
25. Cohen RA, et al. T cells and in situ cryoglobulin deposition in the pathogenesis of lupus nephritis. Clin Immunol. 2008;128(1): 1-7.
26. Li Y, et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus. J Immunol. 2007;178(3): 1938-1947.
27. Biswas PS, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010;120(9): 3280-3295.
28. Shivakumar S, Tsokos GC, Datta SK. T cell receptor a/β expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol. 1989;143(1): 103-112.
29. Koshy M, Berger D, Crow MK. Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest. 1996;98(3): 826-837.
30. Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest. 1996;97(9): 2063-2073.
31. Kyttaris VC, Wang Y, Juang YT, Weinstein A, Tsokos GC. Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. J Immunol. 2007;178(3): 1960-1966.
32. Jeffries MA, Sawalha AH. Epigenetics in systemic lupus erythematosus: Leading the way for specific therapeutic agents. Int J Clin Rheumtol. 2011;6(4): 423-439.
33. Kyttaris VC, Zhang Z, Kampagianni O, Tsokos GC. Calcium signaling in systemic lupus erythematosus T cells: A treatment target. Arthritis Rheum. 2011;63(7): 2058-2066.
34. Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus. 2004;13(5): 391-397.
35. Odegard JM, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med. 2008;205(12): 2873-2886.
36. Vinuesa CG, et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 2005;435(7041): 452-458.
37. Simpson N, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010;62(1): 234-244.
38. Borlado LR, et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J. 2000;14(7): 895-903.
39. Okkenhaug K, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297(5583): 1031-1034.
40. Barber DF, et al. Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3Kinduced systemic lupus but not T cell invasion. J Immunol. 2006;176(1): 589-593.
41. Barber DF, et al. PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med. 2005;11(9): 933-935.
42. Suarez-Fueyo A, Barber DF, Martinez-Ara J, Zea-Mendoza AC, Carrera AC. Enhanced phosphoinositide 3-kinase ? activity is a frequent event in systemic lupus erythematosus that confers resistance to activation-induced T cell death. J Immunol. 2011;187(5): 2376-2385.
43. Suarez-Fueyo A, et al. Inhibition of PI3Kd reduces kidney infiltration by macrophages and ameliorates systemic lupus in the mouse. J Immunol. 2014;193(2): 544-554.
44. Rathmell JC, Elstrom RL, Cinalli RM, Thompson CB. Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur J Immunol. 2003;33(8): 2223-2232.
45. Parsons MJ, Jones RG, Tsao MS, Odermatt B, Ohashi PS, Woodgett JR. Expression of active protein kinase B in T cells perturbs both T and B cell homeostasis and promotes inflammation. J Immunol. 2001;167(1): 42-48.
46. Miyara M, Ito Y, Sakaguchi S. TREG-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol. 2014;10(9): 543-551.
47. Lieberman LA, Tsokos GC. The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J Biomed Biotechnol. 2010;2010: 740619.
48. Wong HK, Kammer GM, Dennis G, Tsokos GC. Abnormal NF-?B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. J Immunol. 1999;163(3): 1682-1689.
49. Kyttaris VC, Juang YT, Tenbrock K, Weinstein A, Tsokos GC. Cyclic adenosine 5'-monophosphate response element modulator is responsible for the decreased expression of c-fos and activator protein-1 binding in T cells from patients with systemic lupus erythematosus. J Immunol. 2004;173(5): 3557-3563.
50. Mishra N, Khan IU, Tsokos GC, Kammer GM. Association of deficient type II protein kinase A activity with aberrant nuclear translocation of the RII β subunit in systemic lupus erythematosus T lymphocytes. J Immunol. 2000;165(5): 2830-2840.
51. Ichinose K, Juang YT, Crispin JC, Kis-Toth K, Tsokos GC. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV. Arthritis Rheum. 2011;63(2): 523-529.
52. Hedrich CM, Rauen T, Tsokos GC. cAMPresponsive element modulator (CREM)a protein signaling mediates epigenetic remodeling of the human interleukin-2 gene: Implications in systemic lupus erythematosus. J Biol Chem. 2011;286(50): 43429-43436.
53. Moulton VR, Grammatikos AP, Fitzgerald LM, Tsokos GC. Splicing factor SF2/ASF rescues IL-2 production in T cells from systemic lupus erythematosus patients by activating IL-2 transcription. Proc Natl Acad Sci U S A. 2013;110(5): 1845-1850.
54. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27: 485-517.
55. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in autoimmunity. Clin Immunol. 2008;127(3): 385-393.
56. Wilson NJ, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9): 950-957.
57. Chen Z, Tato CM, Muul L, Laurence A, O'Shea JJ. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 2007;56(9): 2936-2946.
58. Ivanov, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6): 1121-1133.
59. Kyttaris VC, Zhang Z, Kuchroo VK, Oukka M, Tsokos GC. Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol. 2010;184(9): 4605-4609.
60. Amarilyo G, Lourenco EV, Shi FD, La Cava A. IL-17 promotes murine lupus. J Immunol. 2014;193(2): 540-543.
61. Chen Z, O'Shea JJ. Regulation of IL-17 production in human lymphocytes. Cytokine. 2008;41(2): 71-78.
62. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007;40(1): 1-8.
63. Dong G, et al. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chin Med J (Engl). 2003;116(4): 543-548.
64. Hedrich CM, Crispin JC, Tsokos GC. Epigenetic regulation of cytokine expression in systemic lupus erythematosus with special focus on T cells. Autoimmunity. 2014;47(4): 234-241.
65. Hedrich CM, et al. Stat3 promotes IL-10 expression in lupus T cells through trans-Activation and chromatin remodeling. Proc Natl Acad Sci U S A. 2014;111(37): 13457-13462.
66. Lippe R, et al. CREMa overexpression decreases IL-2 production, induces a T(H)17 phenotype and accelerates autoimmunity. J Mol Cell Biol. 2012;4(2): 121-123.
67. Hedrich CM, et al. cAMP response element modulator alpha controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. Proc Natl Acad Sci U S A. 2012;109(41): 16606-16611.
68. Moulton VR, Holcomb DR, Zajdel MC, Tsokos GC. Estrogen upregulates cyclic AMP response element modulator a expression and downregulates interleukin-2 production by human T lymphocytes. Mol Med. 2012;18: 370-378.
69. Juang YT, et al. Transcriptional activation of the CREM promoter in human T cells is regulated by PP2A mediated dephosphorylation of SP-1 reflects disease activity in patients with systemic lupus erythematosus. J Biol Chem. 2011;286(3): 1795-1801.
70. Hueber W, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52): 52ra72.
71. Genovese MC, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: A phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis. 2013;72(6): 863-869.
72. Crispin JC, Tsokos GC. Human TCR-A β+ CD4- CD8- T cells can derive from CD8+ T cells and display an inflammatory effector phenotype. J Immunol. 2009;183(7): 4675-4681.
73. Hedrich CM, et al. cAMP responsive element modulator (CREM) a mediates chromatin remodeling of CD8 during the generation of CD3+CD4-CD8- T cells. J Biol Chem. 2014;289(4): 2361-2370.
74. de Groot RP, Ballou LM, Sassone-Corsi P. Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: An alternative route to mitogen-induced gene expression. Cell. 1994;79(1): 81-91.
75. Lai ZW, et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J Immunol. 2013;191(5): 2236-2246.
76. Godo M, Sessler T, Hamar P. Role of invariant natural killer T (iNKT) cells in systemic lupus erythematosus. Curr Med Chem. 2008;15(18): 1778-1787.
77. Oishi Y, et al. Selective reduction and recovery of invariant Va24JaQ T cell receptor T cells in correlation with disease activity in patients with systemic lupus erythematosus. J Rheumatol. 2001;28(2): 275-283.
78. Gabriel L, Morley BJ, Rogers NJ. The role of iNKT cells in the immunopathology of systemic lupus erythematosus. Ann N Y Acad Sci. 2009;1173: 435-441.
79. Cho YN, et al. Numerical and functional deficiencies of natural killer T cells in systemic lupus erythematosus: Their deficiency related to disease activity. Rheumatology (Oxford). 2011;50(6): 1054-1063.
80. Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: Role in autoimmune disease and therapeutic opportunities. Immunol Rev. 2008;223: 371-390.
81. Saadoun D, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22): 2067-2077.
82. Koreth J, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22): 2055-2066.
83. Juang YT, et al. Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J Clin Invest. 2005;115(4): 996-1005.
84. Koga T, Ichinose K, Mizui M, Crispin JC, Tsokos GC. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J Immunol. 2012;189(7): 3490-3496.
85. Koga T, et al. CaMK4-dependent activation of AKT/mTOR and CREM-A underlies autoimmunity- Associated Th17 imbalance. J Clin Invest. 2014;124(5): 2234-2245.
86. Delgoffe GM, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4): 295-303.
87. Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J Immunol. 2014;192(9): 4134-4144.
88. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105(12): 4743-4748.
89. Kang J, Huddleston SJ, Fraser JM, Khoruts A. De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR. J Leuk Biol. 2008;83(5): 1230-1239.
90. Battaglia M, Stabilini A, Tresoldi E. Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol Biol. 2012;821: 279-293.
91. Amarilyo G, Iikuni N, Shi FD, Liu A, Matarese G, La Cava A. Leptin promotes lupus T-cell autoimmunity. Clin Immunol. 2013;149(3): 530-533.
92. Procaccini C, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity. 2010;33(6): 929-941.
93. Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A. Cutting edge: Leptin-induced RORgammat expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol. 2013;190(7): 3054-3058.
94. Liu A, La Cava A. Epigenetic dysregulation in systemic lupus erythematosus. Autoimmunity. 2014;47(4): 215-219.
95. Guo Y, Sawalha AH, Lu Q. Epigenetics in the treatment of systemic lupus erythematosus: Potential clinical application. Clin Immunol. 2014;155(1): 79-90.
96. Patel DR, Richardson BC. Dissecting complex epigenetic alterations in human lupus. Arthritis Res Ther. 2013;15(1): 201.
97. Sunahori K, Juang YT, Tsokos GC. Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac a promoter determines CREB binding and activity. J Immunol. 2009;182(3): 1500-1508.
98. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 1990;33(11): 1665-1673.
99. Sunahori K, Nagpal K, Hedrich CM, Mizui M, Fitzgerald LM, Tsokos GC. The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-Activated protein kinase/ extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients. J Biol Chem. 2013;288(30): 21936-21944.
100. Li Y, et al. Overexpression of the growth arrest and DNA damage-induced 45a gene contributes to autoimmunity by promoting DNA demethylation in lupus T cells. Arthritis Rheum. 2010; 62(5): 1438-1447.
101. Grammatikos AP, Ghosh D, Devlin A, Kyttaris VC, Tsokos GC. Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling. PLoS One. 2013;8(8): E74550.
102. Grammatikos AP, et al. A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus. Clin Immunol. 2014;150(2): 192-200.
103. Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 2010;62(7): 2086-2092.
104. Ichinose K, et al. Cutting edge: Calcium/Calmodulin- dependent protein kinase type IV is essential for mesangial cell proliferation and lupus nephritis. J Immunol. 2011;187(11): 5500-5504.
105. Koga T, et al. KN-93, an inhibitor of calcium/ calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3 regulatory T cells in MRL/lpr mice. Autoimmunity. 2014;47(7): 445-450.
106. Wu T, et al. Targeting multiple signaling axes oxidative stress using a synthetic triterpenoid prevents murine lupus nephritis. Arthritis Rheumatol. 2014;66(11): 3129-3139.