Abnormal pattern of tyrosine phosphorylation in unstimulated peripheral blood T lymphocytes from patients with systemic lupus erythematosus

Abstract

Previous reports have shown abnormal responses mediated via the TCR/CD3 pathway in T lymphocytes from systemic lupus erythematosus (SLE) patients. Recently, we and others have reported augmented TCR/CD3-mediated responses in lupus T cells. It is possible that the pattern of downstream biochemical signals triggered by TCR/CD3 ligation may be altered in T lymphocytes from patients with SLE, thus leading to abnormal distal cell responses. In this paper we have examined the phosphorylation of proteins on tyrosine residues in peripheral blood T lymphocytes from a group of SLE patients and controls. We found a lower frequency of constitutively tyrosine phosphorylated 119-and 113-kDa substrates and an enhanced frequency of tyrosine-phosphorylated 66-and 25-kDa proteins in unstimulated cultures of SLE T lymphocytes, suggesting an altered pattern of tyrosine phosphorylation in T cells from patients in vivo. Additionally, the protein tyrosine phosphatase (PTP) activity of CD45 immunoprecipitates was lower in unstimulated lupus T cells and was enhanced after stimulation via the CD3 pathway in lupus but not control T lymphocytes. The present results seem to suggest abnormal regulation of in-vivo tyrosine phosphorylation in T cells from patients with SLE.

Keywords

SLE T cells PTKs phosphatase activity CD3

Get full access to this article

View all access options for this article.

References

Stekman IL et al. Enhanced CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus . Arthritis Rheum 1991; 34: 459–467 .

Blasini AM et al. T lymphocytes from patients with systemic lupus erythematosus show increased response to interleukin-2 after costimulation with OKT3 monoclonal antibody and phorbol esters . Clin Immunol Immunopathol 1994; 70: 66–72 .

Vassilopoulos D , Kovacs B , Tsokos GC . TCR/CD3 complex-mediated signal transduction in T cells and T cell lines from patients with systemic lupus erythematosus . J Immunol 1995; 155: 2269–2281 .

Dayal AK , Kammer GM . The T cell enigma in lupus . Arthritis Rheum 1996; 39: 23–33 .

Abraham N , Miceli MC , Parnes JR , Veillete A . Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck . Nature 1991; 350: 62–66 .

Cooke MP , Abraham KM , Forbush KA , Perlmutter RM . Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn) . Cell 1991; 65: 281–291 .

Davidson D , Chow LMC , Forunell M , Veillete A . Enhancement of Tcell responsiveness by the lymphocyte-specific protein tyrosine kinase p56lck . J Exp Med 1992; 175: 1483–1492 .

Lorenz U , Ravichandran KS , Burakoff SJ , Neel BG . Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyper-responsiveness . Proc Natl Acad Sci USA 1996; 93: 9624–9629 .

Tan EM et al. The revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271–1277 .

10.

Hawker G et al. A reliability study of SLEDAI: A disease activity index for systemic lupus erythematosus . J Rheumatol 1993; 20: 657–660 .

11.

Peyron JF et al. The CD45 protein tyrosine phosphatase is required for the completion of the activation program leading to lymphokine production in the Jurkatt human T cell line . Int Immunol 1991; 3: 1357–1366 .

12.

Trowbridge IS , Thomas ML . CD45: An emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development . Ann Rev Immunol 1994; 12: 85–116 .

13.

Neel BG . Role of phosphatases in lymphocyte activation . Curr Opin Immunol 1997; 9: 405–420 .

14.

De Franco AL . Signaling pathways activated by protein tyrosine phosphorylation in lymphocytes . Curr Op Immunol 1994; 6: 364–371 .

15.

Scholz W et al. lpr T cell hyporesponsiveness to mitogens linked to deficient receptor-stimulated phosphoinositide hydrolysis . J Biol Chem 1992; 263: 1483–1492 .

16.

Matache C et al. Tyrosine phosphorylation in peripheral lyphocytes from patients with systemic lupus erythematosus . Autoimmunity 1996; 24: 217–228 .

17.

Via CS et al. T cell antigen presenting cell interactions in human systemic lupus erythematosus. Evidence for heterogenous expression of multiple defects . J Immunol 1993; 151: 3914–3922 .

18.

Liossis SN , Ding XZ , Dennis GJ , Tsokos GC . Altered pattern of TCR/CD3-mediated protein-tyrosil phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain . J Clin Invest 1998; 101: 1448–1457 .

19.

Sancho J et al. The T cell receptor associated CD3-e protein is phosprorylated upon T cell activation in the two tyrosine residues of a conserved signal transduction motif . Eur J Immunol 1993; 23: 1636–1642 .

20.

Samelson LE , Davidson WF , Morse HC , Klausner RD . Abnormal tyrosine phosphorylation on T-cell receptor in lymphoproliferative disorders . Nature 1986; 324: 674–676 .

21.

Katagiri T et al. Tyrosine phosphorylation of a c-src-like protein is increased in membranes of CD47CD87 T lymphocytes from lpr/lpr mice . Mol Cel Biol 1989; 9: 4914–4922 .

22.

Richards FM , Milner J , Metcalf S . Inhibition of the serine-threonine protein phosphatases PP1 and PP2 in lymphocytes: Effect on mRNA levels for interleukin-2, IL-2Ra, krox-24, p53, hsc70 and cyclophilin . Immunol 1992; 76: 642–647 .

23.

Takeuchi T et al. Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE) . Clin Exp Immunol 1997; 109: 20–26 .