Trends in Immunology
ReviewHow signaling and gene transcription aberrations dictate the systemic lupus erythematosus T cell phenotype
Section snippets
T cells and lupus
T cells play a key role in the regulation of immune responses. Placed in a central position, at the boundary between the sensor and effector arms of the immune system, they finely tune the characteristics, as well as the magnitude and duration, of a given response [1]. T cells regulate the threshold that determines whether an antigen will trigger an immune response; acting through cell contact and the production of soluble mediators, they activate or suppress the function of other immune and
Armed T cells: decreased CD3ζ and preclustered lipid rafts
When T cells from patients with SLE are stimulated through the T cell receptor (TCR), they exhibit an overtly abnormal response. One of the most prominent features is an abnormally fast and high rise in intracellular calcium concentration that is accompanied by increased cytoplasmic protein tyrosine phosphorylation [6]. This enhanced early signaling response occurs when CD3ζ, the main component of the CD3 complex responsible for the antigen-initiated T cell signaling response, is decreased [7].
Upregulated adhesion molecules guide T cells to tissues
Lipid rafts from SLE T cells are not only preclustered, but they also harbor a different array of molecules than rafts found in normal T cells; for instance, they possess FcRγ, Syk, and PLCγ1, all key players in the enhanced calcium response. In addition, the remaining CD3ζ fraction, if any, is located within the rafts. Interestingly, they also harbor adhesion molecules such as the hyaluronic acid (HA) receptor CD44 [18]. As expected, this pattern of expression drives the SLE T cell into an
Aberrant cell signaling has opposing effects on gene expression
As mentioned earlier, SLE T cells receive an erroneous signal when stimulated through their TCR. One of the most obvious consequences of such misinterpretation is a distortion in the pattern of gene expression. Some genes are overexpressed, whereas others fail to be transcribed adequately [22].
Nuclear factor of activated T cells (NFAT), a transcription factor mainly regulated by intracellular calcium concentration, plays a key role in the dysregulation of gene expression in SLE T cells [23].
The balance between CREB and CREM
Cyclic AMP response element-binding protein (CREB) and cyclic AMP response element modulator α (CREMα) are transcriptional regulators that play pivotal roles in the suppression of IL-2 in SLE T cells [34]. They bind in a reciprocal fashion to the −180 position of the IL-2 promoter; phosphorylated CREB increases transcription, whereas CREMα inhibits it. The levels of pCREB are low in SLE T cells, whereas abnormally high amounts of CREMα are found bound to the IL-2 promoter. This anomaly has been
MAP kinases and DNA methylation
In contrast to the augmented intracellular calcium increase, SLE T cells have a conspicuously hampered mitogen-activated protein (MAP) kinase response 39, 40. Specifically, Ras activation has been found to be altered in SLE patients 41, 42. The defect is complex, and numerous alterations, including defective expression of Ras guanyl nucleotide-releasing protein 1 (RasGRP1) and defective PKCδ (protein kinase C) activation, have been linked to it 42, 43. The importance this signaling pathway has
The lupus T cell phenotype: a consequence of wrong signals?
As mentioned earlier, SLE T cells have several abnormalities that substantially alter their signaling mechanisms. An exaggerated early signaling response follows TCR stimulation, but the cell activation process proceeds thereafter in an unbalanced manner. Parallel signaling pathways (e.g. MAP kinase) are not only not increased, but also even diminished. The SLE T cell biochemical defects not only lead to a hyperexcitable cell, but they result in the shaping of a cell that has a completely
Acknowledgements
Work performed in the authors’ laboratory was supported by National Institutes of Health Grants R01 AI042269, RO1 AI049954, and RO1 R01AI068787.
References (48)
Characterization of in vivo mutated T cell clones from patients with systemic lupus erythematosus
Clin. Immunol. Immunopathol.
(1995)Rewiring the T-cell: signaling defects and novel prospects for the treatment of SLE
Trends Immunol.
(2003)Decreased stability and translation of T cell receptor ζ mRNA with an alternatively spliced 3′-untranslated region contribute to ζ chain down-regulation in patients with systemic lupus erythematosus
J. Biol. Chem.
(2005)Autoimmunity in systemic lupus erythematosus: integrating genes and biology
Semin. Immunol.
(2006)Abnormal intracellular distribution of NFAT1 in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features
Clin. Immunol.
(2006)Transcriptional mechanisms underlying lymphocyte tolerance
Cell
(2002)- et al.
Transcriptional repression of interleukin-2 in human systemic lupus erythematosus
Autoimmun. Rev.
(2006) - et al.
Phenotypes of T lymphocytes in systemic lupus erythematosus: decreased cytotoxic/suppressor subpopulation is associated with deficient allogeneic cytotoxic responses rather than with concanavalin A-induced suppressor cells
Clin. Immunol. Immunopathol.
(1983) - et al.
Immunopathogenesis and spectrum of infections in systemic lupus erythematosus
Semin. Arthritis Rheum.
(1996) Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-α
Clin. Immunol. Immunopathol.
(1996)