Fig 1
Structure of the TCR complex. The TCR complex is composed of two TCR chains (αβ or γδ), six-cluster differentiation 3 (CD3) chains, and the coreceptors CD4 or CD8. The TCR in CD4 + T cells recognizes MHC class II molecules expressed in antigen-presenting cells. In contrast, the TCR in CD8 + T cells receives the stimulation of MHC I molecules expressed in nucleated cells. Lck-loaded CD4 or CD8 molecules phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMS) in CD3 chains, essential for signal transduction mediated by the TCR-CD3 complex. After ITMAS is phosphorylated, ZAP-70 interacts with ITMAS phosphotyrosine sites and mediates additional tyrosine phosphorylation. (a) The transmembrane structure of αβTCR complex in CD4 + T cells. (b) The transmembrane structure of γδTCR complex. (c) The transmembrane structure of αβTCR complex in CD8 + T cells. (d) Recombination-activating genes (RAGs) of T cells. Rag1 and Rag2 encode the RAG1
Source publication
Stroke is a severe and life-threatening disease, necessitating more research on new treatment strategies. Infiltrated T lymphocytes, an essential adaptive immune cell with extensive effector function, are crucially involved in post-stroke inflammation. Immediately after the initiation of the innate immune response triggered by microglia/macrophages...
Context in source publication
Context 1
... molecules are recognized by the extracellular domains of CD4 and CD8, the lymphocyte-specific protein tyrosine kinase (Lck), a Src-related protein tyrosine kinase (PTK), binds to the intracellular tails of the CD4 and CD8 chains, accompanied by a reduction in CD45 expression [29]. The structure and components of the TCR complex are summarized in Fig. ...
Citations
... Although the specific details of this pathway in the context of CNS injury are not fully understood, it is essential to note that the pro-inflammatory response of particular cytokines, known as Th1 and Th17 cytokines, can worsen nerve damage caused by inflammation.21,107 This finding leads us to believe that a pathway involving various components such as IL-15, IL-12, CD8 + T cell, CD4 + T cell, NK cell, XCL1, XCR1 + dendritic cell, IFNγ, Th0 cells, Th1 cells, and Th17 cell may have a pro-inflammatory effect after TBI and SCI. ...
Background
Traumatic brain injury (TBI) and spinal cord injury (SCI) are acquired injuries to the central nervous system (CNS) caused by external forces that cause temporary or permanent sensory and motor impairments and the potential for long‐term disability or even death. These conditions currently lack effective treatments and impose substantial physical, social, and economic burdens on millions of people and families worldwide. TBI and SCI involve intricate pathological mechanisms, and the inflammatory response contributes significantly to secondary injury in TBI and SCI. It plays a crucial role in prolonging the post‐CNS trauma period and becomes a focal point for a potential therapeutic intervention. Previous research on the inflammatory response has traditionally concentrated on glial cells, such as astrocytes and microglia. However, increasing evidence highlights the crucial involvement of lymphocytes in the inflammatory response to CNS injury, particularly CD8⁺ T cells and NK cells, along with their downstream XCL1‐XCR1 axis.
Objective
This review aims to provide an overview of the role of the XCL1‐XCR1 axis and the T‐cell response in inflammation caused by TBI and SCI and identify potential targets for therapy.
Methods
We conducted a comprehensive search of PubMed and Web of Science using relevant keywords related to the XCL1‐XCR1 axis, T‐cell response, TBI, and SCI.
Results
This study examines the upstream and downstream pathways involved in inflammation caused by TBI and SCI, including interleukin‐15 (IL‐15), interleukin‐12 (IL‐12), CD8⁺ T cells, CD4⁺ T cells, NK cells, XCL1, XCR1⁺ dendritic cells, interferon‐gamma (IFN‐γ), helper T0 cells (Th0 cells), helper T1 cells (Th1 cells), and helper T17 cells (Th17 cells). We describe their proinflammatory effect in TBI and SCI.
Conclusions
The findings suggest that the XCL1‐XCR1 axis and the T‐cell response have great potential for preclinical investigations and treatments for TBI and SCI.
... tTreg cells, also known as naturally occurring Treg cells (nTreg cells), develop from T cells in the thymus. During differentiation, CD4 + T cells bind to histocompatibility complex II (MHC II) expressed by innate immune cells via T-cell receptors (TCRs) on their surface and stimulate the maturation of nTreg cells via specific cytokines, such as interleukin-2 (IL-2) [20,21]. Compared with other T cells, nTreg cells have a TCR with a greater affinity for MHC/ self-peptide ligands [22]. ...
Intracerebral hemorrhage (ICH) is a common cerebrovascular disease that can lead to severe neurological dysfunction in surviving patients, resulting in a heavy burden on patients and their families. When ICH occurs, the blood‒brain barrier is disrupted, thereby promoting immune cell migration into damaged brain tissue. As important immunosuppressive T cells, regulatory T (Treg) cells are involved in the maintenance of immune homeostasis and the suppression of immune responses after ICH. Treg cells mitigate brain tissue damage after ICH in a variety of ways, such as inhibiting the neuroinflammatory response, protecting against blood‒brain barrier damage, reducing oxidative stress damage and promoting nerve repair. In this review, we discuss the changes in Treg cells in ICH clinical patients and experimental animals, the mechanisms by which Treg cells regulate ICH and treatments targeting Treg cells in ICH, aiming to support new therapeutic strategies for clinical treatment.
... [26][27][28] The activation of T cells is triggered by specific surface receptors that identify antigens and initiate autoimmune responses. 29,30 Compared to innate immune responses, autoreactive T cells can cause direct harm to neurons and glial cells and indirectly affect neuronal function and survival through the release of pro-inflammatory cytokines (IFNγ, IL-1β, TNFα, IL-12) and chemokines (CCL2 and CCL5, among others). 31 CD4 + T cells are categorized into effector (Teff) and regulatory (Treg) T cells, which work together to maintain immune balance. ...
Background
Inflammation can worsen spinal cord injury (SCI), with dendritic cells (DCs) playing a crucial role in the inflammatory response. They mediate T lymphocyte differentiation, activate microglia, and release cytokines like NT‐3. Moreover, DCs can promote neural stem cell survival and guide them toward neuron differentiation, positively impacting SCI outcomes.
Objective
This review aims to summarize the role of DCs in SCI‐related inflammation and identify potential therapeutic targets for treating SCI.
Methods
Literature in PubMed and Web of Science was reviewed using critical terms related to DCs and SCI.
Results
The study indicates that DCs can activate microglia and astrocytes, promote T‐cell differentiation, increase neurotrophin release at the injury site, and subsequently reduce secondary brain injury and enhance functional recovery in the spinal cord.
Conclusions
This review highlights the repair mechanisms of DCs and their potential therapeutic potential for SCI.
... This includes the recruitment of peripheral immune cells to the damaged brain. After an innate immune response initiated by microglia or macrophages, adaptive immune responses associated with T lymphocytes contribute to the complex pathophysiology of stroke 15 . Invasive T cells interact closely with active astrocytes and have a progressive proin ammatory phenotype after ischemic stroke, as evidenced by increased expression of the T cell activation markers CD44 and CD25 and the corresponding transcription factors T-bet and RORC. ...
Background
Conventional observational designs face challenges in studying this relationship, as confounding factors, reverse causality, minor exposure factors and multiple tests cannot be completely eliminated. There is currently a lack of MR studies concerning immune cells and the risk of ischemic stroke. This particular study offers a novel perspective on risk prediction for ischemic stroke.
Objective
To investigate the causal relationship between immune cells and ischemic stroke through Mendelian randomization analysis.
Methods
A complete two-sample Mendelian randomization (MR) analysis was utilized to ascertain the causative relationship between immune cells and ischemic stroke. Using publicly available genetic data, we investigated the causal association between 731 immune cells and the risk of ischemic stroke. Four immune characteristics were included: relative cells (RC), absolute cells (AC), median fluorescence intensity (MFI), and morphological parameters (MP). MR-Egger, Weighted median, Inverse variance weighted (IVW), Weighted mode, Simple mode, and MRPRESS were utilized for analysis. Heterogeneity and horizontal pleiotropy tests were also conducted.
Results
Mendelian randomization analysis showed that 32 of the 731 immune cells had a robust causal relationship with ischemic stroke, among which 15 immune cells such as IgD⁻CD27⁻ %B cell (β = 0.033, 95%CI = 1.002 ~ 1.065, p = 0.037), IgD⁺ CD24 ⁺ AC (β = 0.045, 1.010 ~ 1.082, p = 0.012), CD25hi CD45RA⁻CD4 not Treg %T cell (β = 0.022, 95%CI = 1.002 ~ 1.042, p = 0.028) and soon. CD62L⁻HLADR⁺⁺ monocyte AC (β =-0.053, 95% CI = 0.914 ~ 0.985, p = 0.005), CD33br HLA DR⁺ CD14⁻ AC (β =-0.017, 95% CI = 0.972 ~ 0.995, p = 0.004), EM DN (CD4⁻CD8⁻) %DN (β =-0.014, 95% CI = 0.975 ~ 0.997, p = 0.014), etc. There exists a strong inverse causal link for ischemic stroke.
Conclusion
Our study has demonstrated a close genetic link between immune cells and ischemic stroke. Fifteen immune cells such as IgD⁻CD27⁻ %B cell, IgD⁺ CD24⁺ AC, CD25hi CD45RA⁻CD4 not Treg %T cell have robust positive causal associations with ischemic stroke, and seventeen immune cells such asCD62L⁻ HLA DR⁺⁺ monocyte AC, CD33br HLA DR⁺ CD14⁻ AC, EM DN (CD4⁻CD8⁻) %DN have robust positive causal associations with ischemic stroke. A strong inverse causal relationship with ischemic stroke offers direction for forthcoming clinical studies.
... Among these immune cells, the reprogramming of Tregs is an important regulatory factor in immune responses and inflammatory diseases. Naive CD4+ T cells bind to the major histocompatibility complex II (MHC II) expressed by innate immune cells, regulating helper T cell (Th) differentiation via costimulatory molecules and the release of inflammatory cytokines (26)(27)(28). Typically, Tregs undergo reprogramming under the induction of the inflammatory environment and suppress antitumor immune responses (29,30). ...
Regulatory T cells (Treg), as members of CD4+ T cells, have garnered extensive attention in the research of tumor progression. Treg cells have the function of inhibiting the immune effector cells, preventing tissue damage, and suppressing inflammation. Under the stimulation of the tumor inflammatory microenvironment (IM), the reprogramming of Treg cells enhances their suppression of immune responses, ultimately promoting tumor immune escape or tumor progression. Reducing the number of Treg cells in the IM or lowering the activity of Treg cells while preventing their reprogramming, can help promote the body’s anti-tumor immune responses. This review introduces a reprogramming mechanism of Treg cells in the IM; and discusses the regulation of Treg cells on tumor progression. The control of Treg cells and the response to Treg inflammatory reprogramming in tumor immunotherapy are analyzed and countermeasures are proposed. This work will provide a foundation for downregulating the immunosuppressive role of Treg in the inflammatory environment in future tumor immunotherapy.
Cerebral stroke is one of the leading causes of mortality and disability worldwide. Restoring the cerebral circulation following a period of occlusion and subsequent tissue oxygenation leads to reperfusion injury. Cerebral ischemic reperfusion (I/R) injury triggers immune and inflammatory responses, apoptosis, neuronal damage, and even death. However, the cellular function and molecular mechanisms underlying cerebral I/R-induced neuronal injury are incompletely understood. By integrating proteomic, phosphoproteomic, and transcriptomic profiling in mouse hippocampi after cerebral I/R, we revealed that the differentially expressed genes and proteins mainly fall into several immune inflammatory response–related pathways. We identified that Annexin 2 (Anxa2) was exclusively upregulated in microglial cells in response to cerebral I/R in vivo and oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro. RNA-seq analysis revealed a critical role of Anxa2 in the expression of inflammation-related genes in microglia via the NF-κB signaling. Mechanistically, microglial Anxa2 is required for nuclear translocation of the p65 subunit of NF-κB and its transcriptional activity upon OGD/R in BV2 microglial cells. Anxa2 knockdown inhibited the OGD/R-induced microglia activation and markedly reduced the expression of pro-inflammatory factors, including TNF-α, IL-1β, and IL-6. Interestingly, conditional medium derived from Anxa2-depleted BV2 cell cultures with OGD/R treatment alleviated neuronal death in vitro. Altogether, our findings revealed that microglia Anxa2 plays a critical role in I/R injury by regulating NF-κB inflammatory responses in a non-cell-autonomous manner, which might be a potential target for the neuroprotection against cerebral I/R injury.
