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loss of immune tolerance and widespread inflammation.
T cells play a central role in the inflammatory response, of which CD4+ helper T cells or CD8+ cytotoxic T cells are the most common T cell subsets.
T cell abnormalities such as phenotypic and functional changes in SLE patients are closely related to the pathogenesis of SLE, and this article will introduce the latest research on the biochemical or molecular mechanisms of T cell abnormalities in SLE patients, and explore how these research results can be used for treatment
.
This review was recently published in J Autoimmun.
(impact factor 14.
511).
Mechanisms of T cell abnormalities
1.
T cell phenotypic changes
CD4+ T cells modulate the immune response by providing co-stimulatory signals and cytokines, which are key drivers of the SLE autoantibody response, and the cellolytic activity of CD8+ T cells can cause functional impairment
in SLE patients.
Five major subsets of helper T cells have been identified: Th1, Th2, Th17, Treg (regulatory), and Tfh (follicular helper) cells
.
Imbalance of pathogenic helper T cells (Figure 1), such as uncontrolled expansion of Tfh cells, decreased and dysfunction of CD4+ and CD8+ T cells, are all associated with
SLE pathogenesis.
Fig.
1 Imbalance of helper T cells
2.
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 decreased and Fc receptor γ chain (FcRγ) expression increased, causing the TCR-CD3 complex to conjugate
to splenic tyrosine kinase (Syk) instead of ZAP-70.
Thus, after TCR involvement, a series of downstream abnormalities were observed, including enhanced expression of SLAM-associated protein (SAP), decreased activity of certain kinases, including Lck, PKC, and mitogen-activated protein [MAP] kinases, and abnormally increased
phosphorylation of PLC-γ.
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, which interacts with CD40 expressed by B cells as a secondary signal, which can effectively reduce the activation threshold
of TCR.
3.
Effects of cytokines
Cytokines provide additional signals that cause T cells to behave with different phenotypic and functional outcomes
.
Elevated inflammatory cytokines, including type I
, have been shown to be present.
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 concern among the cytokines produced by T cells, studies have confirmed that the homeostasis and functional maintenance of CD4+ Treg cells require the participation of IL-2 and TGF-β, recent evidence that TGF-β also affects CD8+ Treg cell properties, and it has also been found that IL-2 and TGF-β can directly inhibit pathogenic effector T cells
.
Most of the current research focuses on the role of individual cytokines, and more attention needs to be paid to the synergistic effect
of multiple cytokines.
In addition, the extracellular factors of T cells in SLE also need further research
.
4.
Epigenetic modifications
Epigenetic mechanisms such as DNA methylation, chromatin remodeling, and non-coding RNAs (ncRNAs) have been shown to be key regulators of 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 there are both hypomethylated and hypermethylated cytosine-guanine sites in T cells of SLE patients, so further research is urgently needed to understand the effect
of DNA methylation at different genes and CpG sites on SLE disease activity.
In addition, the degree of deacetylation of histone H3 and H4 in T cells in patients with active SLE was inversely correlated with
SLE disease activity.
Many studies have also revealed abnormal patterns of ncRNAs involved in SLE pathogenesis
.
These results have shown that epigenetic alterations in SLE T cells have a disease-regulating effect, but further research is needed to study their association
with the clinical manifestations of SLE.
5.
Metabolic dysfunction
Metabolic programming determines the fate of T cell differentiation and affects its related functions
.
T cells in patients with SLE have significant metabolic abnormalities
.
Mitochondrial defects in CD4+ T cells can lead to high oxidative stress, altered TCR signaling and enhanced secondary glycolysis,
.
Decreased cytotoxic capacity, degranulation, and decreased cytolysogenic expression of CD8+ T cells lead to an increased
rate of cell infection.
Metabolic disturbances may cause DNT cell expansion in patients with SLE, and one study found a significant reduction
in IL-17+ DNT cells in patients with active SLE treated with the mTOR inhibitor sirolimus.
Potential therapies that target T cells
1.
Target TCR signals
Traditional SLE drugs include glucocorticoids, immunomodulators, and cytotoxic agents, but treatment options targeting T cells are limited
.
Currently, drugs targeting TCR signaling are being developed or used in trials, and clinical trials have shown significant efficacy
in the treatment of mouse models of lupus with inhibitors of Syk, PI3Kδ, and Rho-related protein kinases.
In addition, calcineurin inhibitors block TCR-induced nuclear translocation of activated T cell nuclear factor (NFAT) and are commonly used for off-label treatment of SLE, of which voclosporin was approved by the FDA in January 2021 for the treatment of
.
2.
Target inflammatory factors
Anilimab (type I interferon receptor antibody) was approved by the FDA for SLE
in August 2021.
In addition, clinical trials have shown that low-dose IL-2 is effective in the treatment of SLE, pending its further development and approval
.
There are also many clinical trials using biologics to treat SLE, including antibodies to the IL-23/IL-17 axis, Jak/Stat inhibitors, and more
.
Recent data suggest that drugs that inhibit two non-overlapping targets simultaneously may be more effective, so some clinical trials are considering the simultaneous treatment of both targets with a mixture/two biologics
.
In March 2021, the world's first dual-target biological new drug
in China.
3.
Target metabolic enzymes
Metabolic enzymes in T cells are another therapeutic target of SLE, and drugs such as glucocorticoids have been shown to inhibit glycolysis, and some inhibitors targeting mitochondrial metabolism and lipid metabolism have also been shown to be effective
in treating lupus-susceptible mice.
Since subtle changes in metabolites and metabolomic enzymes can lead to abnormal autoimmune/inflammatory responses, research is still needed to precisely modify them to treat SLE and other autoimmune diseases
.
conclusion
T cells play a key role in the pathogenesis of SLE, and further research into T cell abnormalities and patient stratification will bring hope
for the development of new therapies for SLE.
In addition, in addition to studying the molecular abnormalities of SLE immune cells, attention should also be paid to the study of
organ-resident immune cell defects.
The goal of future clinical trials should be to use targeted T cell therapy while maintaining the necessary functions of T cells (such as cytotoxicity).
References: 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.
