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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Apr 1, 1998; 101(7): 1448–1457.
PMCID: PMC508723

Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain.

Abstract

Cellular immunity aberrations in patients with SLE are underscored by the abnormal early Ag receptor-mediated lymphocyte signal transduction pathway. To further characterize the T cell receptor (TCR)/CD3-initiated signaling defects, we studied 22 patients with SLE, 12 patients with other systemic rheumatic diseases, and 14 normal donors. The early (1 min) TCR/CD3-mediated tyrosine phosphorylation of cellular proteins with a molecular size between 36 and 64 kD was increased in 15 of 21 SLE patients, compared to normal or disease control subjects. The deficiency or absence of a band with a molecular size of approximately 16 kD in the immunoblots of SLE patients led us to investigate the expression of the TCRzeta chain. In immunoblots using anti-zeta antibodies we found that 10 of 22 lupus patients tested lacked the expression of TCRzeta, which was always present in control subjects (P < 0.001). Flow cytometric studies using permeabilized cells confirmed the deficiency or absence of the TCRzeta chain in lupus T cells. Using Northern blots we found that for eight patients tested, the TCRzeta mRNA was missing in three, decreased in three, and apparently normal in two patients (P < 0.003), but was always present in control subjects. Reverse transcriptase-PCR verified Northern blot results. We conclude that TCRzeta chain expression is either decreased or absent in the majority of patients with SLE, but not in patients with other systemic rheumatic diseases, regardless of disease activity, treatment status, or clinical manifestations. The previously described increases in TCR-initiated Ca2+ responses and the herein described increases in TCR-induced protein tyrosine phosphorylation and deficient TCRzeta expression may represent intrinsic defects modulating lupus T cell function.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. [PubMed]
  • Wange RL, Samelson LE. Complex complexes: signaling at the TCR. Immunity. 1996 Sep;5(3):197–205. [PubMed]
  • Vassilopoulos D, Kovacs B, Tsokos GC. TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus. J Immunol. 1995 Aug 15;155(4):2269–2281. [PubMed]
  • Liossis SN, Kovacs B, Dennis G, Kammer GM, Tsokos GC. B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J Clin Invest. 1996 Dec 1;98(11):2549–2557. [PMC free article] [PubMed]
  • Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. [PubMed]
  • Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992 Jun;35(6):630–640. [PubMed]
  • Anderson P, Blue ML, O'Brien C, Schlossman SF. Monoclonal antibodies reactive with the T cell receptor zeta chain: production and characterization using a new method. J Immunol. 1989 Sep 15;143(6):1899–1904. [PubMed]
  • Weissman AM, Hou D, Orloff DG, Modi WS, Seuanez H, O'Brien SJ, Klausner RD. Molecular cloning and chromosomal localization of the human T-cell receptor zeta chain: distinction from the molecular CD3 complex. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9709–9713. [PMC free article] [PubMed]
  • Ponte P, Ng SY, Engel J, Gunning P, Kedes L. Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res. 1984 Feb 10;12(3):1687–1696. [PMC free article] [PubMed]
  • Taupin JL, Anderson P. Activation-induced proteolysis of cytoplasmic domain of zeta in T cell receptors and Fc receptors. Eur J Immunol. 1994 Dec;24(12):3000–3004. [PubMed]
  • Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992 Dec 11;258(5089):1795–1798. [PubMed]
  • Nakagomi H, Petersson M, Magnusson I, Juhlin C, Matsuda M, Mellstedt H, Taupin JL, Vivier E, Anderson P, Kiessling R. Decreased expression of the signal-transducing zeta chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer Res. 1993 Dec 1;53(23):5610–5612. [PubMed]
  • Matache C, Stefanescu M, Onu A, Szegli G, Barel M, Tanaseanu S, Matei I, Bouillie S, Frade R. Tyrosine phosphorylation in peripheral lymphocytes from patients with systemic lupus erythematosus. Autoimmunity. 1996;24(4):217–228. [PubMed]
  • Ohno H, Aoe T, Taki S, Kitamura D, Ishida Y, Rajewsky K, Saito T. Developmental and functional impairment of T cells in mice lacking CD3 zeta chains. EMBO J. 1993 Nov;12(11):4357–4366. [PMC free article] [PubMed]
  • Shores EW, Huang K, Tran T, Lee E, Grinberg A, Love PE. Role of TCR zeta chain in T cell development and selection. Science. 1994 Nov 11;266(5187):1047–1050. [PubMed]
  • Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991 Mar 8;64(5):891–901. [PubMed]
  • Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 1992 Nov 13;71(4):649–662. [PubMed]
  • van Oers NS, Weiss A. The Syk/ZAP-70 protein tyrosine kinase connection to antigen receptor signalling processes. Semin Immunol. 1995 Aug;7(4):227–236. [PubMed]
  • Ohno H, Saito T. CD3 zeta and eta chains are produced by alternative splicing from a common gene. Int Immunol. 1990;2(11):1117–1119. [PubMed]
  • Qian D, Sperling AI, Lancki DW, Tatsumi Y, Barrett TA, Bluestone JA, Fitch FW. The gamma chain of the high-affinity receptor for IgE is a major functional subunit of the T-cell antigen receptor complex in gamma delta T lymphocytes. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11875–11879. [PMC free article] [PubMed]
  • Koyasu S, D'Adamio L, Arulanandam AR, Abraham S, Clayton LK, Reinherz EL. T cell receptor complexes containing Fc epsilon RI gamma homodimers in lieu of CD3 zeta and CD3 eta components: a novel isoform expressed on large granular lymphocytes. J Exp Med. 1992 Jan 1;175(1):203–209. [PMC free article] [PubMed]
  • Küster H, Thompson H, Kinet JP. Characterization and expression of the gene for the human Fc receptor gamma subunit. Definition of a new gene family. J Biol Chem. 1990 Apr 15;265(11):6448–6452. [PubMed]
  • Vivier E, Rochet N, Kochan JP, Presky DH, Schlossman SF, Anderson P. Structural similarity between Fc receptors and T cell receptors. Expression of the gamma-subunit of Fc epsilon RI in human T cells, natural killer cells and thymocytes. J Immunol. 1991 Dec 15;147(12):4263–4270. [PubMed]
  • Anderson P, Caligiuri M, Ritz J, Schlossman SF. CD3-negative natural killer cells express zeta TCR as part of a novel molecular complex. Nature. 1989 Sep 14;341(6238):159–162. [PubMed]
  • Lanier LL, Yu G, Phillips JH. Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature. 1989 Dec 14;342(6251):803–805. [PubMed]
  • Tsokos GC, Balow JE. Cellular immune responses in systemic lupus erythematosus. Prog Allergy. 1984;35:93–161. [PubMed]
  • Shores E, Flamand V, Tran T, Grinberg A, Kinet JP, Love PE. Fc epsilonRI gamma can support T cell development and function in mice lacking endogenous TCR zeta-chain. J Immunol. 1997 Jul 1;159(1):222–230. [PubMed]
  • Shores EW, Love PE. TCR zeta chain in T cell development and selection. Curr Opin Immunol. 1997 Jun;9(3):380–389. [PubMed]
  • Letourneur F, Klausner RD. Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 epsilon. Science. 1992 Jan 3;255(5040):79–82. [PubMed]
  • Hermans MH, Malissen B. The cytoplasmic tail of the T cell receptor zeta chain is dispensable for antigen-mediated T cell activation. Eur J Immunol. 1993 Sep;23(9):2257–2262. [PubMed]
  • Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE. ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. J Exp Med. 1995 Jan 1;181(1):375–380. [PMC free article] [PubMed]
  • Oliver JM, Burg DL, Wilson BS, McLaughlin JL, Geahlen RL. Inhibition of mast cell Fc epsilon R1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol. J Biol Chem. 1994 Nov 25;269(47):29697–29703. [PubMed]
  • Alcocer-Varela J, Alarcón-Segovia D. Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest. 1982 Jun;69(6):1388–1392. [PMC free article] [PubMed]
  • Hoffman T. Natural killer funciton in systemic lupus erythematosus. Arthritis Rheum. 1980 Jan;23(1):30–35. [PubMed]
  • Tsokos GC, Rook AH, Djeu JY, Balow JE. Natural killer cells and interferon responses in patients with systemic lupus erythematosus. Clin Exp Immunol. 1982 Nov;50(2):239–245. [PMC free article] [PubMed]
  • Yamazaki T, Arase H, Ono S, Ohno H, Watanabe H, Saito T. A shift from negative to positive selection of autoreactive T cells by the reduced level of TCR signal in TCR-transgenic CD3 zeta-deficient mice. J Immunol. 1997 Feb 15;158(4):1634–1640. [PubMed]
  • Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, Wiltrout RH, O'Shea JJ, Kudoh S, Klein E, et al. Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res. 1993 Dec 1;53(23):5613–5616. [PubMed]
  • Kammer GM, Khan IU, Malemud CJ. Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymphocytes. J Clin Invest. 1994 Jul;94(1):422–430. [PMC free article] [PubMed]
  • Combadière B, Freedman M, Chen L, Shores EW, Love P, Lenardo MJ. Qualitative and quantitative contributions of the T cell receptor zeta chain to mature T cell apoptosis. J Exp Med. 1996 May 1;183(5):2109–2117. [PMC free article] [PubMed]
  • Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC. Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-alpha. Clin Immunol Immunopathol. 1996 Dec;81(3):293–302. [PubMed]
  • Tsao BP, Cantor RM, Kalunian KC, Chen CJ, Badsha H, Singh R, Wallace DJ, Kitridou RC, Chen SL, Shen N, et al. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest. 1997 Feb 15;99(4):725–731. [PMC free article] [PubMed]

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