COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history

Background:The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)specific T-cells and neutralizing antibodies(nAbs)during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019(COVID-19).We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers.Methods:Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine.All major leukocyte subtypes were enumerated before,during,and after exercise by flow cytometry,and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays,T-cell receptor(TCR)-βsequencing,and SARS-CoV-2 nAb serology.Results:COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise.However,non-infected participants had a significantly reduced mobilization of CD4+and CD8+naive T-cells,as well as CD4+central memory T-cells,after vaccination(synthetic immunity group);this was not seen after vaccination in those with prior SARS-CoV-2 infection(hybrid immunity group).Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent manner.Both groups mobilized T-cells that reacted to spike protein;however,only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens.nAbs increased significantly during exercise only in the hybrid immunity group.Conclusion:These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.

Cross-talk between T-cells and gut-microbiota in neurodegenerative disorders

The emerging role of gut microbiota as a key player in the development of neurodegenerative disorders: Mammals have evolved together with commensal microbiota to establish a symbiotic relationship in which they regulate reciprocally by synthesizing and responding to several common chemical substances. In this regard, gut microbiota constitutes a consortium of bacteria that not only participates in the degradation of nutrients, but also produces metabolites, fatty acids and neurotransmitters that can act on the enzymes and receptors expressed in eukaryotic cells, which considerably affects the physiology of the host and contribute to maintaining homeostasis (Lyte, 2013).

Qingyi decoction attenuates intestinal epithelial cell injury via the calcineurin/nuclear factor of activated T-cells pathway

BACKGROUND Recent studies have demonstrated that dysfunction of the intestinal barrier is a significant contributing factor to the development of severe acute pancreatitis(SAP).A stable intestinal mucosa barrier functions as a major anatomic and functional barrier,owing to the balance between intestinal epithelial cell(IEC)proliferation and apoptosis.There is some evidence that calcium overload may trigger IEC apoptosis and that calcineurin(CaN)/nuclear factor of activated Tcells(NFAT)signaling might play an important role in calcium-mediated apoptosis.AIM To investigate the potential mechanisms underlying the therapeutic effect of Qingyi decoction(QYD)in SAP.METHODS A rat model of SAP was created via retrograde infusion of sodium deoxycholate.Serum levels of amylase,tumor necrosis factor(TNF-α),interleukin(IL)-6,D-lactic acid,and diamine oxidase(DAO);histological changes;and apoptosis of IECs were examined in rats with or without QYD treatment.The expression of the two subunits of CaN and NFAT in intestinal tissue was measured via quantitative realtime polymerase chain reaction and western blotting.For in vitro studies,Caco-2 cells were treated with lipopolysaccharide(LPS)and QYD serum,and then cell viability and intracellular calcium levels were detected.RESULTS Retrograde infusion of sodium deoxycholate increased the severity of pancreatic and intestinal pathology and the levels of serum amylase,TNF-α,and IL-6.Both the indicators of intestinal mucosa damage(D-lactic acid and DAO)and the levels of IEC apoptosis were elevated in the SAP group.QYD treatment reduced the serum levels of amylase,TNF-α,IL-6,D-lactic acid,and DAO and attenuated the histological findings.IEC apoptosis associated with SAP was ameliorated under QYD treatment.In addition,the protein expression levels of the two subunits of CaN were remarkably elevated in the SAP group,and the NFATc3 gene was significantly upregulated at both the transcript and protein levels in the SAP group compared with the control group.QYD significantly restrained CaN and NFATc3 gene expression in the intestine,which was upregulated in the SAP group.Furthermore,QYD serum significantly decreased the LPS-induced elevation in intracellular free Ca^(2+)levels and inhibited cell death.CONCLUSION QYD can exert protective effects against intestinal mucosa damage caused by SAP and the protective effects are mediated,at least partially,by restraining IEC apoptosis via the CaN/NFATc3 pathway.

Cytotoxic T-cells as imaging probes for detecting glioma

Tumor vaccination using tumor-associated antigenprimed dendritic cells(DCs)is in clinical trials.Investigators are using patients’own immune systems to activate T-cells against recurrent or metastatic tumors.Following vaccination of DCs or attenuated tumor cells,clinical as well as radiological improvements have been noted due to migration and accumulation of cytotoxic T-cells(CTLs).CTLs mediated tumor cell killing resulted in extended survival in clinical trails and in preclinical models.Besides administration of primed DCs or attenuated or killed tumors cells to initiate the generation of CTLs,investigators have started making genetically altered T-cells(CTLs)to target specific tumors and showed in vivo migration and accumulation in the implanted or recurrent tumors using different imaging modalities.Our groups have also showed the utilization of both in vivo and in vitro techniques to make CTLs against glioma and used them as imaging probes to determine the sites of tumors.In this short review,the current status of vaccination therapy against glioma and utilization of CTLs as in vivo imaging probes to determine the sites of tumors and differentiate recurrent glioma from radiation necrosis will be discussed.

Effects of the Cytotoxic T-Cells on the Dynamics of Co-Infection of HIV-1 and Mycobacterium tuberculosis

Enhancement of the Human Immunodeficiency Virus (HIV) specific cytotoxic T-cells mechanisms in an HIV-1 and Mycobacterium tuberculosis (Mtb) co-infected individual seems to improve the clinical picture of an individual by reducing Acquired Immuno Deficiency Syndrome (AIDS) state progression rate. In this paper, we develop a system of deterministic differential equations representing the immune cells involved in an HIV-1 and Mtb co-infected individual. Results show that although the non-lytic arm of the HIV-1 cytotoxic T-cells affects the co-infection dynamics more than the lytic factors, a combination of both factors results in a more positive reduced progression to the AIDS state. This is due to the increased protection of the CD4+ T-cells by the CTL mechanisms by further reducing infections and replications by the HIV. Thus, HIV-1 specific CTLs mechanisms’ involvement is here recommended to be part of a solution to the HIV and Mtb co-infection problems.

Efficient Numerical Scheme for the Solution of HIV Infection CD4^(+)T-Cells Using Haar Wavelet Technique

In this paper,Haar collocation algorithmis developed for the solution of first-order ofHIV infection CD4^(+)T-Cells model.In this technique,the derivative in the nonlinear model is approximated by utilizing Haar functions.The value of the unknown function is obtained by the process of integration.Error estimation is also discussed,which aims to reduce the error of numerical solutions.The numerical results show that the method is simply applicable.The results are compared with Runge-Kutta technique,Bessel collocation technique,LADM-Pade and Galerkin technique available in the literature.The results show that the Haar technique is easy,precise and effective.

Tumor Antigen Specific Activation of Primary Human T-Cells Expressing a Virally Encoded Chimeric T-Cell Receptor Specific for p185HER2

We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral producer cells were established in the GALV-based PG13 packaging cell line. Ficoll purified human peripheral blood lymphocytes (PBL) were virally transduced using an optimized protocol incorporating activation with immobilized anti-CD3/anti-CD28 monoclonal anti- bodies, followed by viral infection in the presence of fibronectin fragment CH296. Transduced cells were co-cultured with human tumor cell lines that overexpress (SK-OV-3) or underexpress (MCF7) p185HER2 to assay for antigen specific im- mune responses. Both CM+ and CD8+ T-cells transduced with the N29γ or N29ζ chTCR demonstrated HER2-specific anti- gen responses, as determined by release of Th1 like cytokines, and cellular cytotoxicity assays. Our results support the fea- sibility of adoptive immunotherapy with genetically modified T-cells expressing a chTCR specific for p185HER2.

ICAM-1 depletion in the center of immunological synapses is important for calcium releasing in T-cells

T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-βsignaling

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

Absence of enhancement in a lesion does not preclude primary central nervous system T-cell lymphoma:A case report

BACKGROUND Primary central nervous system lymphoma(PCNSL)is a non-Hodgkin lymphoma that originates in the central nervous system(CNS)and is exclusively limited to the CNS.Although most PCNSLs are diffuse large B-cell lymphomas,primary CNS T-cell lymphomas(PCNSTLs)are rare.PCNSTLs typically demonstrate some degree of enhancement on contrast-enhanced magnetic resonance imaging(MRI).To the best of our knowledge,non-enhancing PCNSTL has not been reported previously.CASE SUMMARY A 69-year-old male presented to the neurology department with complaints of mild cognitive impairment and gradual onset of left lower leg weakness over a span of two weeks.Initial MRI showed asymmetric T2-hyperintense lesions within the brain.No enhancement was observed on the contrast-enhanced T1 image.The initial diagnosis was neuro-Behçet’s disease.Despite high-dose steroid therapy,no alterations in the lesions were identified on initial MRI.The patient’s symptoms deteriorated further.An MRI performed one month after the initial scan revealed an increased lesion extent.Subsequently,brain biopsy confirmed the diagnosis of PCNSTL.The patient underwent definitive combined chemoradiotherapy.However,the patient developed bacteremia and died of septic shock approximately three months after diagnosis.CONCLUSION The absence of enhancement in the lesion did not rule out PCNSTL.A biopsy approach is advisable for pathological confirmation.

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

Plasmacytosis mimicking multiple myeloma in angioimmunoblastic T-cell lymphoma:A case report and review of literature

BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL)is a common subtype of peripheral T-cell lymphoma.Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia.Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis.These tumors mimic plasma cell myelomas,hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.CASE SUMMARY A 78-year-old woman experienced poor appetite,weight loss of 5 kg,fatigue 2 months before presentation,and shortness of breath 2 d before presentation,but no fever or night sweats.Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions,approximately>2 cm in size,with rubbery consistency and no tenderness.Blood tests revealed anemia and thrombocytopenia,lactate dehydrogenase level of 153 U/L,total protein level of 10.9 g/dL,albumin to globulin ratio of 0.2,and immunoglobulin G level more than the upper limit of 3000 mg/dL.The free kappa and lambda light chain concentrations were 451 and 614 mg/L,respectively.A pathological examination confirmed the diagnosis of AITL.The initial treatment was the cyclophosphamide,epirubicin,vincristine,and prednisolone regimen.Following this treatment,pleural effusion was controlled,and the patient was discharged in a stable condition and followed up in our outpatient department.CONCLUSION This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia.A precise diagnosis of AITL requires a comprehensive evaluation,involving clinical,immunophenotypic,and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.

Monomorphic epitheliotropic intestinal T-cell lymphoma with bone marrow involved: A case report

BACKGROUND Monomorphic epithelial intestinal T-cell lymphoma(MEITL)is a rare type of peripheral T-cell lymphoma.The clinical manifestations are diarrhea,abdominal pain,perforation and an abdominal mass.CASE SUMMARY We present a 52-year-old female patient who was diagnosed with MEITL.Further disease progression was observed after multiline chemotherapy.Eventually,the patient died of a severe infection.CONCLUSION MEITL is a rare intestinal primary T-cell lymphoma with aggressive behavior,a high risk of severe life-threatening complications,and a poor prognosis.

New perspective on the treatment of rheumatic arthritis based on“strengthening body resistance(FúZhèng)”in the theory of co-inhibitory receptor-regulated T-cell immunity

Co-inhibitory receptors serve as crucial regulators of T-cell function,playing a pivotal role in modulating the delicate balance between immune tolerance and autoimmunity.Initially identified in autoimmune disease models,co-inhibitory receptors,including CTLA-4,PD-1,TIM-3,and TIGIT,were found to be integral to immune regulation.Their blockade or absence in these models resulted in the induction or exacerbation of autoimmune diseases.Additionally,scholars have observed that co-inhibitory receptors on lymphocytes hold the potential to influence the prognosis in the context of chronic inflammation.Consequently,the blocking of co-suppressor receptors has emerged as a novel therapeutic approach for inhibiting refractory inflammatory diseases,particularly rheumatoid arthritis.From the standpoint of traditional Chinese medicine(TCM),the treatment of rheumatoid arthritis based on the“strengthening body resistance(FúZhèng)”theory can be construed as the regulation of co-suppressor receptors to modulate the body’s immune function in combating chronic inflammation.This article provides a succinct overview of the role of co-suppressor receptors in anti-inflammatory processes and explores the research prospects of co-suppressor receptor intervention in the treatment of rheumatoid arthritis.The exploration integrates the“strengthening body resistance(FúZhèng)”theory with relevant Chinese medicine formulations.

Influencing factors and solution strategies of chimeric antigen receptor T-cell therapy(CAR–T)cell immunotherapy

Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.

Investigation of the Clinical Diagnostic Significance of the T-Cell Test for Tuberculosis combined with Erythrocyte Sedimentation Test in Pulmonary Tuberculosis

Objective:To investigate the clinical diagnostic significance of peripheral blood T-cell test(T-spot test)for tuberculosis(TB)infection combined with erythrocyte sedimentation rate(ESR)in pulmonary TB.Methods:41 patients with a clinical diagnosis of TB during hospitalization from January 2020 to April 2023 in our hospital were selected as the experimental group,and 45 patients without TB(bronchopneumonia patients)were selected as the control group.The diagnostic specificity,sensitivity,and accuracy of the T-spot TB test,ESR test,and the combined test of the two were calculated respectively.Results:The sensitivity,specificity,and accuracy of the T-spot TB test combined with ESR for the diagnosis of TB in the experimental group were significantly higher than the individual results of the T-spot TB test and ESR test alone(P<0.05).Conclusion:The T-spot TB test combined with the ESR test for TB diagnosis has greater clinical value than carrying out the tests individually.

The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4＋CD25＋ regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment

The frequency and T-cell receptor beta-chain variable （TCRBV） patterns of peripheral CD4＋CD25＋ regulatory T-cells （Tregs） are ambiguously altered in chronic hepatitis B （CHB） patients following tenofovir disoproxil fumarate （TDF） treatment. Moreover, the clinical significance of these parameters in relation to hepatitis B e antigen （HBeAg） seroconversion （SC） is largely unknown. In this study, the circulation of Tregs in HBeAg-positive CHB patients was determined by flow cytometry, and the molecular profiles of frequent TCRBV patterns of Tregs were analyzed using a gene melting spectral pattern. The parameters, such as Treg frequency, the number of skewed TCRBV patterns, hepatitis B virus （HBV） DNA levels, and alanine aminotransferase （ALT） levels, were analyzed by comparing their associations in seroconverting and non-seroconverting patients following TDF treatment. The Treg frequency was significantly correlated with the ALT level in seroconverting but not in non-seroconverting patients. Similarly, skewed TCRBV patterns were remarkably associated with HBV DNA levels in the SC group. Six TCRBV families （BV3, BV11, BV12, BV14, BV20, and BV24） were more prevalent than other TCRBV members in seroconverting patients pretreated with TDF, while BV12, BV15, and BV22 were predominant in non-seroconverting patients during TDF treatment. Taken together, the preferential TCRBV patterns may be associated with immune responses related to SC. The dynamic frequency and skewed TCRBV patterns of peripheral Tregs could contribute to predicting SC in CHB patients. Moreover, the conserved TCRBV complementarity-determining region （CDR3） motif may be targeted to develop personalized immunotherapy for CHB patients.

Regulatory T-cells promote hepatitis B virus infection and hepatocellular carcinoma progression

Regulatory T-cells (Tregs), known for their immune suppressive function, have been reported in higher numbers, with activated phenotypes and greater potency, in hepatitis B virus (HBV)-related liver diseases than in normal conditions. The numbers, phe-notypes, and function of intrahepatic and/or tumor-infiltrating Tregs in HBV-related liver diseases also differ from those of Tregs in the peripheral blood. By inhibiting the function of effector T-cells (Teffs), Tregs play a substantial role in the formation and maintenance of the liver's suppressive microenvironment, which might account for the progression of HBV-related hepatitis and hepatocellular carcinoma (HCC). In acute hepatitis B virus infection, Tregs can safeguard the liver from damage at the cost of prolonged antiviral processes, which results in chronic HBV infection in the liver. Furthermore, Tregs play a role in the development of cirrhosis, the transformation of cirrhosis to HCC, and the progression and metastasis of HCC. Higher levels of Tregs in the peripheral blood and/or tumor sites signify a poorer prognosis in HBV-related liver conditions, and observational data from mouse models and human patients support the theory that depleting Tregs may be therapeutic in HBV-related liver diseases by inducing antiviral and antitumor immunity.

Parameters estimation of HIV infection model of CD4＋ T-cells by applying orthonormal Bernstein collocation method

The HIV infection model of CD4＋ T-cells corresponds to a class of nonlinear ordinary differential equation systems. In this study, we provide the approximate solution of this model by using orthonormal Bernstein polynomials （OBPs）. By applying the proposed method, the nonlinear system of ordinary differential equations reduces to a nonlinear system of algebraic equations which can be solved by using a suitable numerical method such as Newton＇s method. We prove some useful theorems concerning the convergence and error estimate associated to the present method. Finally, we apply the proposed method to get the numerical solution of this model with the arbitrary initial conditions and values. Furthermore, the numerical results obtained by the suggested method are compared with the results achieved by other previous methods. These results indicate that this method agrees with other previous methods.

A numerical method for the solutions of the HIV infection model of CD4＋ T-cells

In this paper, the human immunodeficiency virus （HIV） infection model of CD4＋ T-cells is considered. In order to numerically solve the model problem, an operational method is proposed. For that purpose, we construct the operational matrix of integration for bases of Taylor polynomials. Then, by using this matrix operation and approximation by polynomials, the HIV infection problem is transformed into a system of algebraic equations, whose roots are used to determine the approximate solutions. An important feature of the method is that it does not require collocation points. In addition, an error estimation technique is presented. We apply the present method to two numerical examples and compare our results with other methods.