Five major abnormal mechanisms of T cells in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by
loss of immune tolerance and widespread inflammation.
T cells play a central role in the inflammatory response, where CD4+ helper T cells or CD8⁺ Cytotoxic T cells are the most common subset
of T cells.
T cell abnormalities such as phenotypic and functional changes in SLE patients are closely related
to the pathogenesis of SLE.

T cell phenotypic changes 

CD4+ T cells regulate the immune response by providing co-stimulatory signals and cytokines, and are key drivers of SLE autoantibody response, and the cytolytic activity of CD8+ T cells can cause functional impairment
in SLE patients.
Five major helper cell subsets have been identified: Th1, Th2, Th17, Treg (regulatory), and Tfh (follicular helper) cells
.
Imbalances in pathogenic helper T cells, such as uncontrolled expansion of Tfh cells, reduction and loss of function of CD4+ and CD8+ T cells, are all involved The incidence of SLE is associated
.

Abnormal T cell activation

 T cell activation involves 3 signals, including T cell receptor (TCR) (signal 1), co-stimulation (signal 2), and cytokine stimulation (signal 3).

T cell CD3ζ levels in SLE are reduced, and Fc receptors γ chains ( Increased expression of FcRγ), causing the TCR-CD3 complex to be coupled to splenic tyrosine kinase (Syk) rather than ZAP-70.

Thus, following TCR involvement, a range of downstream abnormalities were observed, including enhanced expression of SLAM-associated protein (SAP), certain kinases (including Lck, PKC and mitogen-activated protein [MAP] kinase) activity decreased, and PLC-γ phosphorylation was abnormally increased
.
The reconnected downstream signaling pathway causes increased calcium influx, which enhances TCR signaling and alters the expression
of genes such as CD40L.
CD40L is a co-stimulatory molecule expressed by T cells, and its interaction with CD40 expressed by B cells can be effectively reduced as a secondary signal Activation threshold
for TCR.

Effects of cytokines 

Cytokines provide additional signaling that causes T cells to exhibit different phenotypes and functional outcomes
.
Elevated inflammatory cytokines have been shown in SLE, including interferon type I, IL-6, and IL-23
.
Interferon promotes the activation, proliferation and differentiation of CD4+ T cells, and IL-6 and IL-23 promote the function of
Th17 cells.
IL-2 and TGF-β are also of interest among the cytokines produced by T cells, and studies have confirmed that CD4+Treg cells require IL-2 and for homeostasis and function maintenance TGF-β involved, and recent evidence suggests that TGF-β also affects CD8+Treg cell properties, and IL-2 has also been found and TGF-β can directly inhibit pathogenic effector T cells
.

Most of the current research focuses on the role of single cytokines, and more attention needs to be paid to the synergistic effect
of the combination of multiple cytokines.
In addition, extracellular factors of T cells in SLE require further study
.

Epigenetic modifications 

Epigenetic mechanisms such as DNA methylation, chromatin remodeling, and noncoding RNAs (ncRNAs) have proven to be key regulators in the immune response
.
In the past, it was thought that the DNA of T cells in SLE was generally hypomethylated, but studies have found that T in SLE patients There are both hypomethylated and highly methylated cytosine-guanine sites in cells, so further research is urgently needed to understand the DNA methylation of different genes and CpG sites for SLE Effects of
disease activity.
In addition, the degree of deacetylation of histones H3 and H4 of T cells in SLE active patients is similar to that of SLE Disease activity is inversely correlated
.
Many studies have also revealed that abnormal ncRNAs patterns are involved in the pathogenesis
of SLE.
These results have shown that epigenetic alterations in SLE T cells have a disease-modifying effect, but further research is needed to link them to the clinical manifestations of SLE
.

Metabolic dysfunction 

Metabolic programming determines the fate of T cell differentiation and affects their associated functions
.
T cells in SLE patients have obvious metabolic abnormalities
.
Mitochondrial defects in CD4+ T cells lead to high oxidative stress, altered TCR signaling, and enhanced secondary glycolysis, while glutamine hydrolysis affects Tfh cell development and iron accumulation is enhanced CD4+ T cells differentiate
into Tfh cells.
Decreased cytotoxicity, degranulation, and decreased cytoplasmin expression of CD8+ T cells lead to increased
cell infection rates.
Metabolic disturbances may cause DNT cell expansion in patients with SLE, and one study found that patients with active SLE were treated with the mTOR inhibitor sirolimus IL-17+ DNT cells were significantly reduced
.

In conclusion, T cells play a key role in the pathogenesis of SLE, and further study of T cell abnormalities and patient stratification will bring hope
for the development of new therapies for SLE.

References:

【1】Li H, Boulougoura A, Endo Y, Tsokos GC.
Abnormalities of T cells in systemic lupus erythematosus: new insights in pathogenesis and therapeutic strategies[J].
J Autoimmun.
2022 Jul 21:102870.
doi: 10.
1016/j.
jaut.
2022.
102870.
Epub ahead of print.
PMID: 35872102.