Stem cell-like memory T cells:Role in viral infections and autoimmunity

Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization.In case of chronic viral diseases such as human immunodeficiency virus-1,CD4+T_(SCM) cells,serve as major reservoirs of the latent virus.However,during immune activation and functional exhaustion of effector T cells,these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection.More recently,these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion.Similarly,studies are also investigating their pathological role in driving autoimmune responses.However,there are several gaps in the understanding of the role of T_(SCM) cells in viral and autoimmune diseases to make them potential therapeutic targets.In this minireview,we have attempted an updated compilation of the dyadic role of these complex T_(SCM) cells during such human diseases along with their biology and transcriptional programs.

Role of OX40 in mechanisms of memory T cells in islet transplant tolerance

Objective To investigate the role of OX40 in the mechanisms of memory T cells in islet transplant tolerance. Methods The expression of OX40 on native, like memory and memory CD8 + T cells was detected by RT - PCR. Splenic T ceels from B6 mice were injected into Rag - / - mice via the tail vein,and the Rag mice were divided into three groups ( n = 8 each) :

Low-dose intralesional injection of 5-fluorouracil and triamcinolone reduces tissue resident memory T cells in chronic eczema

BACKGROUND Tissue resident memory T(TRM)cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil(5-FU)and triamcinolone(TA)with those associated with TA alone for the treatment of chronic eczema.METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only.Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes.All patients were followed up monthly for up to 1 year.RESULTS No serious adverse event was observed in either group.Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment,the relapse rate was significantly lower in the 5-FU+TA group than in the TA group.Histological examination showed significantly fewer CD8^(+)and CD103^(+)T cells but not CD4^(+)T cells in the 5-FU+TA group.CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of T_(RM) cells in the lesional skin and the relapse rate of chronic eczema.

High percentage of bone marrow CD8^(+)tissue-resident-like memory T cells predicts inferior survival in patients with acute myeloid leukemia

Tissue-resident memory T(TRM)cells infiltrating solid tumors could influence tumor progression and the response to immune therapies.However,the proportion and prognostic value of TRM cells in the bone marrow(BM)of patients with acute myeloid leukemia(AML)are unclear.In this study,we used flow cytometry to assay the phenotype of 49 BM samples from patients newly diagnosed with AML(ND-AML).We found that the BM CD8^(+)effector memory(TEM)cells highly expressed CD69(CD8^(+)TRM-like T cells),and their percentage was significantly increased in patients with ND-AML compared with that in healthy individuals(HI).The high percentage of CD8^(+)TRM-like subset was associated with poor overall survival in our ND-AML cohort.The Kaplan–Meier Plotter database verified a significantly reduced survival rate among patients with high expression of CD8^(+)TRM-like T cell characteristic genes(CD8A,CD69,and TOX),especially the M4 and M5 subtypes.Phenotypic analysis revealed that the BM CD8^(+)TRM-like subpopulation exhibited exhausted T cell characteristics,but its high expression of CD27 and CD28 and low expression of CD57 suggested its high proliferative potential.The single-cell proteogenomic dataset confirmed the existence of TRM-like CD8^(+)T cells in the BM of patients with AML and verified the high expression of immune checkpoints and costimulatory molecules.In conclusion,we found that the accumulation of BM CD8^(+)TRM-like cells could be an immune-related survival prediction marker for patients with AML.

Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders

The skin is the largest organ of the body.The establishment of immunological memory in the skin is a crucial component of the adaptive immune response.Once naive T cells are activated by antigen-presenting cells,a small fraction of them differentiate into precursor memory T cells.These precursor cells ultimately develop into several subsets of memory T cells,including central memory T(TCM)cells,effector memory T(TEM)cells,and tissue resident memory T(TRM)cells.TRM cells have a unique transcriptional profile,and their most striking characteristics are their long-term survival(longevity)and low migration in peripheral tissues,including the skin.Under physiological conditions,TRM cells that reside in the skin can respond rapidly to pathogenic challenges.However,there is emerging evidence to support the vital role of TRM cells in the recurrence of chronic inflammatory skin disorders,including psoriasis,vitiligo,and fixed drug eruption,under pathological or uncontrolled conditions.Clarifying and characterizing the mechanisms that are involved in skin TRM cells will help provide promising strategies for reducing the frequency and magnitude of skin inflammation recurrence.Here,we discuss recent insights into the generation,homing,retention,and survival of TRM cells and share our perspectives on the biological characteristics of TRM cells in the recurrence of inflammatory skin disorders.

Memory T cells: strategies for optimizing tumor immunotherapy

Several studies have demonstrated that memory T cells including stem cell memory (Tscm) T cells and central memory (Tcm) T cells show superior persistence and antitumor immunity compared with effector memory T (Tem) cells and effector T (Teff) cells.Furthermore,the Tcm/Teff ratio has been reported to be a predictive biomarker of immune responses against some tumors.Thus,a system-level understanding of the mechanisms underlying the differentiation of effector and memory T cells is of increasing importance for developing immunological strategies against various tumors.This review focuses on recent advances in efficacy against tumors,the origin,formation mechanisms of memory T cells,and the role of the gut microbiota in memory T cell formation.Furthermore,we summarize strategies to generate memory T cells in (ex) vivo that,might be applicable in clinical practice.

Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status

BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ T_(RM) may play a role in the immunogenicity in MSI-H CRC(BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of T_(RM) cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.

Function of Helper T Cells in the Memory CTL-mediated Anti-tumor Immunity

To investigate the role of CD4 + helper T (Th) cells in the memory CTL-mediated anti-tumor immunity, the RAG-1 gene knock out mice were adoptively transferred with OT-1 cells to generate the memory CTL, the C57BL/6 mice immunized with the epitope peptide of OVA specific Th cells and with different adjuvants were adoptively transferred with these memory-CTLs, and then the animals were challenged with tumor cells EG7. It was found that although the simple immunization of mice with the epitope peptide of the OVA specific Th cells could generate more effect CTL, but this effect was not so strong enough to resist completely the challenges with tumor cells. Nevertheless, the memory CTL-mediated anti-tumor immune effect required the helps of Th1 and Th2 cells. The cross-regulation between Th1 and Th2 cells seemed to be beneficial for the host to generate more effector CTL for mounting an efficient anti-tumor response. It concluded that the interaction between Th1 and Th2 cells might be more important than the single subset of Th cells in the memory CTL-mediated anti-tumor immune response. More attention should be paid in this regard for the future studies.

Defect of CD8^+ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

IL-12 priming plays an important role in stimulation of CD8^＋ effector T cells and development of CD8^＋ memory T （Tm） cells. However, the functional alteration of CD8^＋ Tm cells developed in the absence of IL-12 priming is elusive. In this study, we investigated the capacity of secondary expansion of CD8~ Tm cells developed from transgenic OT I CD8^＋ T cells. The latter cells were in vitro and in vivo stimulated by ovalbumin （OVA）-pulsed dendritic cells [DCovA and （IL-12^-/-）DCovA] derived from wild-type C57BL/6 and IL-12 gene knockout mice, respectively. We demonstrated that IL-12 priming is important not only in CD8^＋ T cell clonal expansion, but also in generation of CD8^＋ Tm cells with the capacity of secondary expansion upon antigen re-encounter. However, IL-12 signaling is not involved in CD8^＋ Tm cell survival and recall responses. Therefore, this study provides useful information for vaccine design and development. Cellular ＆ Molecular Immunology.

Pien Tze Huang alleviates Concanavalin A-induced autoimmune hepatitis by regulating intestinal microbiota and memory regulatory T cells

BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T(mTreg)cells functional levels.METHODS Following induction of the AIH mouse model induced by Concanavalin A(Con A),prophylactic administration of PTH was given for 10 d.The levels of mTreg cells were measured by flow cytometry,and intestinal microbiota was analyzed by 16S rRNA analysis,while western blotting was used to identify activation of the toll-like receptor(TLR)2,TLR4/nuclear factor-κB(NF-κB),and CXCL16/CXCR6 signaling pathways.RESULTS In the liver of mice with AIH,PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ,tumor necrosis factor-alpha,interleukin(IL)-1β,IL-2,IL-6,and IL-21 expression.Simultaneously,PTH stimulated the abundance of helpful bacteria,promoted activation of the TLR2 signal,which may enhance Treg/mTreg cells quantity to produce IL-10,and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways.CONCLUSION PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH,which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.

Memory CD8+ T cell differentiation in viral infection: A cell for all seasons

Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specific CD8+ T cells play an important role in the course and outcome of these viral infections and it is hypothesized that altered or impaired differentiation of virus- specific CD8+ T cells contributes to the development of persistence and/or disease progression. A deeper understanding of the mechanisms responsible for functional differentiation of CD8+ T cells is essential for the generation of successful therapies aiming to strengthen the adaptive component of the immune system.

Mucosal COVID-19 vaccines:Risks,benefits and control of the pandemic

Based on mucosal immunization to promote both mucosal and systemic immune responses,next-generation coronavirus disease 2019(COVID-19)vaccines would be administered intranasally or orally.The goal of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines is to provide adequate immune protection and avoid severe disease and death.Mucosal vaccine candidates for COVID-19 including vector vaccines,recombinant subunit vaccines and live attenuated vaccines are under development.Furthermore,subunit protein vaccines and virus-vectored vaccines have made substantial progress in preclinical and clinical settings,resulting in SARS-CoV-2 intranasal vaccines based on the previously successfully used nasal vaccines.Additional to their ability to trigger stable,protective immune responses at the sites of pathogenic infection,the development of‘specific’mucosal vaccines targeting coronavirus antigens could be an excellent option for preventing future pandemics.However,their efficacy and safety should be confirmed.

Comprehensive analysis of endoplasmic reticulum stress-related mechanisms in type 2 diabetes mellitus

BACKGROUND The endoplasmic reticulum(ER)is closely related to a wide range of cellular functions and is a key component to maintain and restore metabolic health.Type 2 diabetes mellitus(T2DM)is a serious threat to human health,but the ER stress(ERS)-related mechanisms in T2DM have not been fully elucidated.AIM To identify potential ERS-related mechanisms and crucial biomarkers in T2DM.METHODS We conducted gene set enrichment analysis(GSEA)and gene set variation analysis(GSVA)in myoblast and myotube form GSE166502,and obtained the differentially expressed genes(DEGs).After intersecting with ERS-related genes,we obtained ERS-related DEGs.Finally,functional analyses,immune infiltration,and several networks were established.RESULTS Through GSEA and GSVA,we identified several metabolic and immune-related pathways.We obtained 227 ERS-related DEGs and constructed several important networks that help to understand the mechanisms and treatment of T2DM.Finally,memory CD4^(+)T cells accounted for the largest proportion of immune cells.CONCLUSION This study revealed ERS-related mechanisms in T2DM,which might contribute to new ideas and insights into the mechanisms and treatment of T2DM.

Distortion of memory Vδ2 γδ T cells contributes to immune dysfunction in chronic HIV infection

γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus （HIV） infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδT cell, which may account for the dysfunction of Vδ2 γδT cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR＋ γδ T cells and CD38＋HLA-DR＋ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.

MHC class Ⅰ-independent activation of virtual memory CD8 T cells induced by chemotherapeutic agent-treated cancer cells

Cancer cells can evade immune recognition by losing major histocompatibility complex(MHC)class Ⅰ.Hence,MHC class Ⅰ-negative cancers represent the most challenging cancers to treat.Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment However,it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class Ⅰ and whether such MHC class Ⅰ-independent CD8 T-cell activation can be exploited for cancer immunotherapy.Here,we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class Ⅰ-independent manner and that these activated CD8 T cells exhibit virtual memory(VM)phenotypes.Consistently,in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells.Mechanistically,MHC class Ⅰ-independent activation of CD8 T cells requires cell-cell contact and activation of the PI3K pathway.VM CD8 T cells contribute to a superior therapeutic effect on MHC class Ⅰ-deficient tumors.Using humanized mouse models or primary human CD8 T cells,we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class Ⅰ.In conclusion,CD8 T cells can be directly activated in an MHC class Ⅰ-independent manner by chemotherapy-treated cancers,and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class Ⅰ-deficient cancers.

IL-15 increases the frequency of effectormemory CD8^(+) T cells in rhesus monkeys immunized with HIV vaccine

Several studies have suggested that interleukin(IL)-15 is a promising adjuvant that promotes cellular immunity when administered with human immunodeficiency virus(HIV)vaccine.Here we evaluated the effect of IL-15 plasmid on HIV-specific immune responses,especially cellular immunity,in eight rhesus monkeys.These monkeys were immunized three times with HIV DNA vaccine with or without IL-15 plasmid and boosted with recombinant Tiantan strain vaccinia virus-based HIV vaccine(rTV)22 weeks after the first immunization.Although we did not detect any significant differences in the HIV-specific CD81 T-cell response between monkeys with IL-15 coimmunization and monkeys with HIV vaccine alone,our results showed that the frequency of effector CD8^(+) memory T cells in the peripheral blood was significantly higher in monkeys with IL-15 coimmunization than those with HIV vaccine alone at almost all of the time points examined.Furthermore,the titers of anti-HIV antibodies were higher in Group T than those in Group C after rTV boosting.These findings in rhesus monkeys suggest that IL-15 may be useful as a cytokine adjuvant for HIV vaccine.

TRAF2 regulates T cell immunity by maintaining a Tpl2-ERK survival signaling axis in effector and memory CD8 T cells

Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.

A critical epitope in CD147 facilitates memory CD4^(+) T-cell hyper-activation in rheumatoid arthritis

The abnormal activation of CD4^(+)CD45RO+memory T(Tm)cells plays an important role in the pathogenesis of rheumatoid arthritis(RA).Previous studies have shown that CD147 participates in T-cell activation.However,it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients.In this study,we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients.The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis.Using a structural–functional approach,we depicted the interface between 5A12 and CD147.This allowed us to identify two critical residues,Lys63 and Asp65,as potential targets for RA treatment,as the double mutation K63A/D65A inhibited Tm-cell activation,mimicking the neutralization by 5A12.This study provides not only a theoretical basis for a“CD147-Tm/Osteoclast-RA chain”for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.

Origin of CD8^+ Effector and Memory T Cell Subsets

It is well accepted that CD8＋ T cells play a pivotal role in providing protection against infection with intracellular pathogens and some tumors. In many cases protective immunity is maintained for long periods of time （immunological memory）. Over the past years, it has become evident that in order to fulfill these multiple tasks, distinct subsets of effector and memory T cells have to be generated. Until today, however, little is known about the underlying mechanisms of subset differentiation and the timing of lineage fate decisions. In this context, it is of special importance to determine at which level of clonal expansion functional and phenotypical heterogeneity is achieved. Different models for T cell subset diversification have been proposed; these differ mainly in the time point during priming and clonal expansion （prior, during, or beyond the first cell division） when differentiation programs are induced. Recently developed single-cell adoptive transfer technology has allowed us to demonstrate that individual precursor cell still bears the full plasticity to develop into a plethora different T cell subsets. This observation targets the shaping of T cell subset differentiation towards factors that are still operative beyond the first cell division. These findings have important implications for vaccine development, as the modulation of differentiation patterns towards distinct subsets could become a powerful strategy to enhance the efficacy and quality of vaccines. Cellular ＆ Molecular Immunology.

Tissue-resident lymphocytes: from adaptive to innate immunity

Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and natural killer(NK)cells constantly and uniformly recirculate.Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues,termed tissue-resident memory T(TRM)cells and tissue-resident NK(trNK)cells,observed in various organs owing to improved techniques.TRM cells populate a wide range of peripheral organs,including the skin,sensory ganglia,gut,lungs,brain,salivary glands,female reproductive tract,and others.Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs(SLOs)as well,leading to revision of the classic theory that they exist only in peripheral organs.trNK cells have been identified in the uterus,skin,kidney,adipose tissue,and salivary glands.These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells.In this review,we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes,with a particular focus on CD8+memory T cells,and describe some advances regarding unconventional T cells(invariant NKT cells,mucosal-associated invariant T cells(MAIT),andγδT cells)and the emerging family of trNK cells.Specifically,we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.