Role Of CD4 Research Articles

Antigen specificity of clonally-enriched CD8+ T cells in multiple sclerosis.

CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. These findings shed vital insight into the role of CD8+ T cells in MS and pave the way towards disease biomarkers and therapeutic targets.

The prevalence of Tuberculosis in HIV patients and their correlation with CD4+ count in a tertiary care hospital in Rishikesh, gateway to the Himalayas

IntroductionTuberculosis is the most common serious opportunistic infection in HIV-positive patients. TB can occur at any time during the course of HIV infection. The estimated number of people living with HIV in India in 2019 was 23.48 lakh. With an estimated 2.5 million cases, or 195 cases per 1 lakh people, India has the highest incidence of tuberculosis cases worldwide, accounting for about 23% of all cases, according to MOHFW India. Information about HIV/TB co-infection is still scarce in India, especially in the hilly areas of Uttarakhand. Material and methodsIn this retrospective study, subjects are the patients who are diagnosed with MTB in HIV-positive patients of all age groups and sex and were followed up from January 2021 till August 2022 in a tertiary referral hospital AIIMS Rishikesh.Diagnosis of MTB was based on clinical, laboratory, and neuroimaging signs, and HIV was based on dot blot, immunochromatographic, and chemiluminescence assay. ResultA total of 520 patients screened for HIV were positive. Out of which 145 were MTB in which 133 had pulmonary tuberculosis and 12 had extra-pulmonary tuberculosis. The patients' average age was 35.5 years. Among males, females and transgender, 97 (66.89%), 46 (31.72%) and 2 (1.38%) have both TB and HIV co-infections respectively.Mean CD4 count prior to ATT was 350.21, After completion was 486.48. The prevalence of Tuberculosis among HIV positive cases was 23.8%.Baseline and latest CD4 count was conducted before and after ART and ATT treatment. It was observed that there was significant increase in the CD4 count after treatment. ConclusionHIV co-infection with TB is higher in this region. There is a role of CD4+ count in the prognosis and progression of the disease. More strategic measures are required for early diagnosis and treatment of HIV to combat MTB.

7967 Ruxolitinib Prevents Immune-Checkpoint Inhibitor-Related Diabetes Mellitus Via Inhibition Of Pathogenic IL-21 And IFNγ-Producing CD4+ T Cells

Abstract Disclosure: N.L. Huang: None. J. Ortega: None. S.J. Wang: None. L.N. Scott: None. K. Kimbrell: None. E. McCarthy: None. J. Olay: None. J.N. Nguyen: None. K. Kim: None. J. Lee: None. M.G. Lechner: None. The use of immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment landscape for many advanced cancers by leveraging immune activation through the blockade of checkpoint proteins, including programmed death protein-1 (PD-1). Unfortunately, autoimmune attack of healthy tissue can occur in up to 60% of patients. ICI-induced Type 1 diabetes mellitus (ICI-T1DM) is a rare but life-threatening adverse event during ICI therapy that leads to rapid destruction of pancreatic islets, hyperglycemia, and lifetime dependence on insulin. While cytotoxic CD8+ T cells are recognized as important players in ICI-T1DM, the role for CD4+ helper T cells in disease pathogenesis is less well understood. Using a mouse model of ICI-autoimmunity, in which male and female NOD mice treated with anti-PD-1 (10mg/kg/day, i.p., twice weekly) develop multi-organ autoimmune infiltrates including insulitis and DM, we identified interleukin-21 (IL-21) and interferon gamma (IFNγ) CD4+ T cells as key contributors to ICI-T1DM. Antibody depletion of CD4+ T cells in NOD mice significantly delayed the onset of ICI-T1DM. Immunophenotyping of pancreatic islet infiltrates in ICI-treated mice revealed increased IL-21+ IFNγ+ CD4+ T follicular helper (Tfh; ICOS+ PD1+ CXCR5+) and T peripheral helper (Tph; ICOS+PD1+ CXCR5- CXCR6+) cells. In vitro, IL-21 increased effector CD8+ T cell function and IFNγ promoted production of T cell-attracting chemokines CXCL9, CXCL10, and CXCL16 by macrophages. Given the potential role for IL-21 and IFNγ to amplify ICI-DM progression, we sought to target these signaling pathways as potential interventions. Genetic inhibition of IL-21 or IFNγ signaling in NOD mice reduced insulitis and DM in anti-PD-1 treated mice. Considering that IL-21 and IFNγ act through JAK/STAT signaling in immune cells, we proposed to block this pathway to prevent ICI-DM using ruxolitinib, a clinically available JAK1/2 inhibitor. Indeed, ruxolitinib blocked STAT3 and STAT1 phosphorylation in mouse splenocytes in response to IL-21 or IFNγ, respectively, and completely protected ICI-treated NOD mice from DM. Finally, in a syngeneic tumor model, use of ruxolitinib after initiation of anti-PD-1 therapy did not abrogate ICI anti-tumor effects. Taken together, these data suggest that IL-21 and IFNγ producing CD4+ T cells are important drivers of ICI-T1DM, and that the use of JAK inhibitors may be a promising clinical intervention to reduce ICI-T1DM toxicities in patients. Presentation: 6/2/2024

Hypertension and Cognitive Dysfunction in a Pregnant Rat Model of PE; a Role for CD4+ T Cells.

Preeclampsia (PE) is associated with hypertension (HTN) during pregnancy and activated CD4+ T cells, inflammatory cytokines, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Having had COVID-19 (CV) during pregnancy is associated with an increased incidence of a PE-like phenotype. Both PE and CV have long-lasting neurological implications and studies show that nonpregnant COVID patients produce AT1-AA. We have shown that CD4+ T cells from PE women cause a PE phenotype in nude athymic rats. In this study, we sought to examine the role of CD4+ T cells from PE with a CV History (Hx) to contribute to a PE phenotype and to determine the importance of CD4+ T cells in cognitive dysfunction during pregnancy. At delivery, blood and placentas were collected, and one million placental CD4+ T cells from each PE and each normotensive patient, with (NT) or without (NP) a CV (Hx) during pregnancy, were isolated, purified, and injected i.p. into a gestational day (GD) 12 pregnant nude athymic rat (one patient/rat). At GD19, blood pressure (MAP) and circulating factors were assessed in recipient rats. Cognitive function and memory were assessed using Novel Object Recognition and Barnes Maze tests, respectively. Placental ACE-2 activity and AT1-AA were measured from COVID Hx patients. A one- or two-way ANOVA with Bonferroni's multiple comparisons test was used for statistical analysis. Blood pressure was increased in patients with PE, with or without COVID, compared to NT patients. There were no significant changes in placental ACE activity in patients with COVID Hx with or without PE. AT1-AA was elevated in PE patients and in both PE and NT COVID Hx compared to control NP. In pregnant recipient rats, MAP increased in CV Hx PE (113±2, n=8) compared to CV Hx NT (101±5, n=6). PE and PE CV Hx CD4+ T Cell recipient rats exhibited impaired memory and cognitive dysfunction (p < 0.05), compared to control groups. Recipient rats of PE CV Hx CD4+ T cells had elevated AT1-AA compared to NT CV Hx recipients. Both COVID Hx groups and recipients of PE CD4+ T cells had elevated TNF alpha compared to NP. Our findings indicate that pregnant patients with a Hx of COVID during pregnancy produce AT1-AA, with or without PE. Recipients of CD4+ T cells from PE with or without a CV Hx during pregnancy cause HTN and elevated AT1-AA. TNF-α is elevated in PE and in CV Hx NT and PE recipients. Interestingly, recipients of T cells from PE patients with or without a Hx of CV had worse cognitive function during pregnancy, compared to recipient rats of NP CD4+ T cells. These data demonstrate the importance of CD4+ T cells in HTN and impaired neurological function during PE in the presence or absence of a prior COVID-19 infection during pregnancy.

CD8+ tissue-resident memory T cells are expanded in primary Sjögren’s disease and can be therapeutically targeted by CD103 blockade

ObjectiveTissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and...

Implications of CD154 and Its Receptors in the Pathogenesis and Treatment of Systemic Lupus Erythematosus.

CD154, also known as CD40 ligand, is a costimulatory molecule involved in humoral and adaptive immune responses upon pairing with its classical receptor, CD40. The CD154/CD40 dyad is a key participant in the pathogenesis of many autoimmune diseases, including systemic lupus erythematosus (SLE). In SLE, the major cells at play, T and B lymphocytes, are shown to overexpress CD154 and CD40, respectively. Subsequently, these cells and other CD40-positive cells engage in numerous effector functions contributing to SLE development. With the recent identification of additional receptors for CD154, all belonging to the integrin family, the role of CD154 in SLE is more complex and calls for deeper investigation into its biological significance. Many therapeutic strategies directed against the CD154/CD40 couple have been deployed for the treatment of SLE and proved efficient in animal models and human studies. However, the incidence of thromboembolic complications in patients treated with these anti-CD154/CD40 antibodies halted their further clinical assessments and called for another class of therapies targeting these molecules. Second-generation antibodies directed against CD154 or CD40 are showing promising results in the advanced stages of clinical testing. Our review presents a thorough description of CD154 and its receptors, CD40 and the integrin family members in SLE pathogenesis. All these elements of the CD154 system represent important therapeutic targets for the treatment of SLE.

IL-4-Induced Gene 1: A Potential Player in Myocardial Infarction.

Myocardial infarction (MI), a severe outcome of cardiovascular disease, poses a serious threat to human health. Uncontrolled inflammation and excessive cardiomyocyte death, following an infarction event, significantly contribute to both the mortality rate and complications associated with MI. The protein IL-4-induced gene 1 (IL4I1 or FIG1) serves as a natural inhibitor of innate and adaptive immunity, playing a crucial role in CD4+ T cell differentiation, macrophage polarization, and ferroptosis inhibition. Previous studies have linked IL4I1 to acute MI. This review summarizes evidence from both basic and clinical research, highlighting IL4I1 as a critical immunoregulatory enzyme that not only regulates inflammatory responses, but also potentially mitigates MI-induced damage.

Huang-Jin-Shuang-Shen Decoction promotes CD8+ T-cell-mediated anti-tumor immunity by regulating chemokine CXCL10 in gastric cancer

BackgroundResearch on immunotherapy for gastric cancer is currently receiving significant attention, with particular emphasis on the role of CD8+ T cells in anti-tumor immune responses. In recent years, the importance of the chemokine CXCL10 in promoting anti-tumor immunity has been increasingly recognized because it plays a crucial role in recruiting CD8+ T cells to the tumor microenvironment. The Huang-Jin-Shuang-Shen (HJSS) Decoction, a Chinese medicine, has been used as an adjuvant drug for gastric cancer chemotherapy. Its mechanism of action may be related to the activation of anti-tumor immunity. PurposeTo assess the role of the HJSS Decoction in regulating the immune microenvironment of gastric cancer and elucidate its mechanism. Study design/methodsUltra-high performance liquid chromatography Q Exactive-mass spectrometry was used to analyze the main components of the HJSS Decoction and evaluate the therapeutic effect of the HJSS Decoction synergized with 5-fluorouracil (5-FU) on gastric cancer. The proportions of CD8+ T cells and killing markers were determined using flow cytometry. Mechanisms of action and targets were screened using network pharmacology. The level of CXCL10 was detected using enzyme-linked immunosorbent assay and western blot, and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) related signaling pathway was detected in vitro. The target function was validated by siRNA transfection. ResultsThe combination of HJSS Decoction and 5-FU demonstrated a synergistic effect in impeding the progression of subcutaneous gastric cancer. This was achieved through the facilitation of apoptosis and suppression of proliferation. Furthermore, HJSS Decoction exhibited the ability to enhance the population of CD8+ T cells and augment their cytotoxic capabilities, both in laboratory settings and in living organisms. Notably, HJSS Decoction upregulated the expression of CXCL10, and mechanistically, it activated the NFκB-related signaling pathway to initiate subsequent transcription of chemokines. ConclusionThe present study aimed to investigate the pharmacological mechanism of the HJSS Decoction and its potential clinical application in inhibiting gastric cancer in mice. HJSS Decoction can cooperate with 5-FU to inhibit gastric cancer, and the optimal dose is medium. HJSS Decoction exerts anti-tumor immunity by activating the NFκB-related signaling pathway and promoting the expression of CXCL10, which in turn recruits CD8+ T cells into the tumor immune microenvironment. Overall, these findings provide valuable evidence for the potential clinical application of HJSS Decoction.

Role of CD86 on granulocyte in mediating the effect of Genus Roseburia on periodontitis.

This study aimed to explore the causal link between the gut microbiota and periodontitis, and to delineate and quantify the intermediary role of immune cells, so as to provide new insights into the pathogenesis, prevention and treatment of periodontitis. We employed a two-sample Mendelian randomization (MR) approach to analyze the genetic predictors of gut microbiota composition (covering 412 gut microbiota taxa and functions) and periodontitis (involving 4,784 cases and 272,252 controls) derived from genome-wide association study (GWAS) datasets. A subsequent two-step MR analysis was conducted to evaluate the extent to which immune cell traits (encompassing 731 immune cell characteristics) mediate the influence of gut microbiota on periodontitis risk. Our analysis implicated nine gut microbiota taxa as causal factors in periodontitis susceptibility (p < 0.05). Notably, the Genus Roseburia was identified as exerting a protective effect against periodontitis, partially mediated through the upregulation of CD86 expression on granulocytes, with an 8.15% mediation effect observed. Our findings establish a causal relationship between the gut microbiota and periodontitis, highlighting the protective role of Roseburia against this condition. A notable proportion of this protective effect is mediated via the upregulation of CD86 on granulocytes. It can provide new ideas for the pathogenesis, prevention and treatment for periodontitis through exploring the causal link between the gut microbiota and periodontitis, and describing and quantifying the intermediary role of immune cells.

Abstract P193: Adoptive transfer of placental CD4+ T Cells from preeclamptic patients with a history of COVID-19 causes hypertension and cognitive dysfunction postpartum in a pregnant rat model of preeclampsia

Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with activated CD4+ T cells, impaired cognitive function, and changes in cerebral blood flow (CBF) autoregulation. Previously, PE women have been shown to develop neurovascular and cardiovascular disorders earlier in life than those that had uneventful pregnancy. COVID-19 (CV) during pregnancy is associated with an increase incidence of the PE phenotype and is also associated with chronic neurovascular and cardiovascular consequences. Previously, we showed adoptive transfer of placental CD4+ T cells from PE women into athymic nude pregnant rats causes a PE phenotype, however we don’t know the role of CD4+ T cells to cause long-term neurovascular or cardiovascular consequences in PE in the presence or absence of a history (Hx) of COVID-19 during pregnancy. Therefore, we hypothesize that CD4+ T cells from PE patients with and without a Hx of CV causes hypertension and neurovascular dysfunction compared to CD4+ T cells from normotensive patients. One million placental CD4+ T cells from Normotensive (NT), CV Hx NT, and PE patients with or without a CV Hx were isolated and injected interperitoneally (i.p.) into pregnant nude athymic rats on gestational day (GD) 12. Dams were allowed to deliver and aged 12-weeks after delivery. At 12-weeks postpartum, blood pressure (MAP) was measured; CBF autoregulation was measured by laser Doppler flowmetry. The Barnes maze and the novel object recognition behavioral assays were used to assess cognitive function 12-weeks postpartum. A two-way ANOVA was used for statistical analysis. At 12-weeks postpartum, MAP increased in CV Hx PE (153±6, n=7, p&lt;0.05) and PE (150±5 mmHg, n=5, p&lt;0.05) compared to CV Hx NT (121±6, n=6) and NT (116±6 mmHg, n=6), respectively. Behavioral analysis showed CV Hx PE and PE exhibited impaired memory and learning (P&lt;0.05) compared to either NT group. Our findings indicate that rat recipients of CD4+ T cells from PE patients in the presence or absence of CV Hx have HTN and cognitive dysfunction in the postpartum period compared to recipients of control CD4 + T cells. These data indicate the importance of CD4+ T cells in long-term consequences of PE and COVID infection during pregnancy.

The histone methyltransferase Mixed-lineage-leukemia-1 drives T cell phenotype via Notch signaling in diabetic tissue repair.

Immune cell-mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+ T cells in normal or diabetic wound repair; however, the imbalance of CD4+ Th17/Tregs has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase Mixed-lineage-leukemia-1 (MLL1) directly regulates the Th17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Furthermore, we found that Notch receptor signaling regulates CD4+ Th cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+ T cells resulted in the loss of CD4+ Th cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling was upregulated in wound CD4+ Th cells, driving CD4+ T cells toward the Th17 cell phenotype. Treatment of diabetic wound CD4+ T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+ Th17 cells and IL-17A. This is the first study to our knowledge to identify the MLL1-mediated mechanisms responsible for regulating the Th17/Treg balance in normal and diabetic wounds and to define the complex role of Notch signaling in CD4+ T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+ Th cells may decrease pathologic inflammation through regulation of CD4+ T cell differentiation.

CD4, but not Cxcr6, is necessary for control of Pneumocystis murina infection

CD4+ T cells are critical to control of Pneumocystis infection, and Cxcr6 has been shown to be upregulated in these cells during infection, but the roles of CD4 and Cxcr6 in this setting are undefined. To explore this, mice deficient in CD4 or Cxcr6 expression were utilized in a co-housing mouse model that mimics the natural route of Pneumocystis infection. Organism load and anti-Pneumocystis antibodies were assayed over time, and immunohistochemistry, flow cytometry, and quantitative PCR were used to characterize host immune responses during infection. CD4 was found to be necessary for clearance of Pneumocystis murina, though partial control was seen in it's absence; based on ThPOK expression, double negative T cells with T helper cell characteristics may be contributing to this control. Using a Cxcr6 deficient mouse expressing gfp, control of infection in the absence of Cxcr6 was similar to that in heterozygous control mice. It is noteworthy that gfp + cells were seen in the lungs with similar frequencies between the 2 strains. Interferon-ɣ and chemokine/ligands Cxcr3, Cxcl9, and Cxcl10 increased during P. murina infection in all models. Thus, CD4, but not Cxcr6, is needed for clearance of P. murina infection.

Preparation of biochar from pyrolysis of soybean straw at different pyrolysis temperature for cadmium removal from wastewater and pyrolysis gas investigation

The Cd2+ adsorption performance of biochar derived from soybean straw pyrolysis at 400–600 °C is investigated. Langmuir model can accurately describe the Cd2+ adsorption data with adsorption amount of 47.30 mg/g with pH=5. Cd2+ adsorption kinetic process could be analyzed using Pseudo-second-order. Biochar has large Cd2+ wastewater treatment volume, based on column adsorption experiment. The π-electrons play an important role in Cd2+ adsorption, based on adsorption mechanism analysis. Biochar has good stability after three cycles. Biochar also has good application potential used in lithium ion battery anode with specific capacity of 132 mA g−1. Besides, pyrolysis gas is recycled in the preparation process of biochar with heating value of the 12.10 MJ/Nm3. These results indicate that soybean straw waste is converted into sustainable adsorbent for Cd2+ wastewater treatment.

The roles of CD4+ T cell help, sex, and dose in the induction of protective CD8+ T cells against a lethal poxvirus by mRNA-LNP vaccines

The role of CD4+ T-cells in the induction of protective CD8+ T-cells by mRNA Lipid Nanoparticle (LNP) vaccines is unknown. We used B6 or Tlr9-/- mice depleted or not of CD4+ T-cells and LNP vaccines loaded with mRNAs encoding the ectromelia virus (ECTV) MHC Class I H-2 Kb-restricted immunodominant CD8+ T-cell epitope TSYKFESV (TSYKFESV mRNA-LNP) or the ECTV EVM158 protein, which contains TSYKFESV (EVM-158 mRNA-LNP). Following prime and boost with 10 μg of either vaccine, Kb-TSYKFESV-specific CD8+ T-cells fully protected male and female mice from ECTV at 29- (both mRNA-LNPs) or 90-days (EVM158 mRNA-LNP) post boost (dpb) independently of CD4+ T-cells. However, at 29 dpb with 1 μg mRNA-LNPs, males had lower frequencies of Kb-TSYKFESV-specific CD8+ T-cells and were much less well protected than females from ECTV, also independently of CD4+ T-cells. At 90 dpb with 1 μg EVM158 mRNA-LNPs, the frequencies of Kb-TSYKFESV-specific CD8+ T-cells in males and females were similar, and both were similarly partially protected from ECTV, independently of CD4+ T-cells. Therefore, at optimal or suboptimal doses of mRNA-LNP vaccines, CD4+ T-cell help is unnecessary to induce protective anti-poxvirus CD8+ T-cells specific to a dominant epitope. At suboptimal doses, protection of males requires more time to develop.

Clinical and microbiological characteristics of persistent Staphylococcus aureus bacteremia, risk factors for mortality, and the role of CD4+ T cells

This study evaluated the determinants of mortality and the T cell immune response in patients with persistent Staphylococcus aureus bacteremia (SAB). This was a prospective cohort study and patients with confirmed SAB were enrolled from 2008 to 2020. We compared clinical, microbiological, and genotypic features between surviving and deceased patients with persistent SAB. The concentrations of cytokines and the proportions of IFN-γ secreting CD4+ T cells were measured serially during the bacteremia period. Of the 1760 patients, 242 had persistent bacteremia (PB), and 49 PB patients died within 30 days. In the multivariate analysis, the APACHE II score and female sex were independently associated with 30 days mortality. The level of IL-10 was significantly increased in the plasma of patients with a high Pitt bacteremia score and those who died within 12 weeks from the index day. The proportion of IFN-γ-secreting CD4+ T cells were the highest just before the positive-to-negative conversion of blood cultures in patients with a low Pitt bacteremia score and those who survived for 12 weeks. The level of IL-10 is correlated with clinical outcomes in PB patients. IFN-γ secreting CD4+ T cells might play a pivotal role in SAB PB.

Psoriatic arthritis subtypes are phenocopied in humanized mice.

Psoriatic arthritis (PsA) is a complex inflammatory disease that challenges diagnosis and complicates the rational selection of effective therapies. Although T cells are considered active effectors in psoriasis and PsA, the role of CD8+ T cells in pathogenesis is not well understood. We selected the humanized mouse model NSG-SGM3 transgenic strain to examine psoriasis and PsA endotypes. Injection of PBMCs and sera from patients with psoriasis and PsA generated parallel skin and joint phenotypes in the recipient mouse. The transfer of human circulating memory T cells was followed by migration and accumulation in the skin and synovia of these immunodeficient mice. Unexpectedly, immunoglobulins were required for recapitulation of the clinical phenotype of psoriasiform lesions and PsA domains (dactylitis, enthesitis, bone erosion). Human CD8+ T cells expressing T-bet, IL-32 and CXCL14 were detected by spatial transcriptomics in murine synovia and by immunofluorescence in the human PsA synovia. Importantly, depletion of human CD8+ T cells prevented skin and synovial inflammation in mice humanized with PsA peripheral blood cells. The humanized model of psoriasis and PsA represents a valid platform for accelerating the understanding of disease pathogenesis, improving the design of personalized therapies, and revealing psoriatic disease targets.

Immune crossroads in atherosclerosis: role of CD8+ T Cells, CD4+ T cells and toll-like receptors in lower extremity arterial disease

Immune crossroads in atherosclerosis: role of CD8+ T Cells, CD4+ T cells and toll-like receptors in lower extremity arterial disease

A GITRL-mTORC1-GM-CSF Positive Loop Promotes Pathogenic Th17 Response in Primary Sjögren Syndrome.

Glucocorticoid-induced tumor necrosis factor receptor superfamily-related protein (GITR), with its ligand (GITRL), plays an important role in CD4+ T cell-mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren syndrome (pSS). Patients with pSS and healthy controls were recruited. Serum GITRL and Th17-related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sjögren models and recombinant adeno-associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo. Serum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17-related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte-macrophage colony-stimulating factor positive (GM-CSF+) CD4+ T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM-CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL-mTORC1-GM-CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice. Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL-mTORC1-GM-CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS.

Deciphering CD4+ T cell-mediated responses against cancer.

It'sbeen long thought that CD8+ cytotoxic T cells play a major role in T cell-mediated antitumor responses, whereas CD4+ T cells merely provide some assistance to CD8+ T cells as the "helpers."In recent years, numerous studies support the notion that CD4+ T cells play an indispensable role in antitumor responses. Here, we summarize and discuss the current knowledge regarding the roles of CD4+ T cells in antitumor responses and immunotherapy, with a focus on the molecular and cellular mechanisms behind these observations. These new insights on CD4+ T cells may pave the way to further optimize cancer immunotherapy.

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy

BackgroundMucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear.Patients and methodsIn this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC.ResultsThe proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders’ peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis.ConclusionCD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.