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.
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2022, Clinical ImmunologyCitation Excerpt :For example, exposure of T cells to self-antigen can result in their inactivation through a process called anergy that involves the ubiquitination and subsequent degradation of key molecules [10]. Interestingly, gross alterations in the expression levels of signaling molecules have been observed in T cells from patients with SLE [4]. An early observation from the Tsokos' Lab demonstrated that T cells from patients with SLE have reduced or absent levels of CD3ζ [11].
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