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.

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.

Curcumin alleviates experimental colitis via a potential mechanism involving memory B cells and Bcl-6-Syk-BLNK signaling

BACKGROUND Immune dysfunction is the crucial cause in the pathogenesis of inflammatory bowel disease(IBD),which is mainly related to lymphocytes(T or B cells,including memory B cells),mast cells,activated neutrophils,and macrophages.As the precursor of B cells,the activation of memory B cells can trigger and differentiate B cells to produce a giant variety of inducible B cells and tolerant B cells,whose dysfunction can easily lead to autoimmune diseases,including IBD.AIM To investigate whether or not curcumin(Cur)can alleviate experimental colitis by regulating memory B cells and Bcl-6-Syk-BLNK signaling.METHODS Colitis was induced in mice with a dextran sulphate sodium(DSS)solution in drinking water.Colitis mice were given Cur(100 mg/kg/d)orally for 14 consecutive days.The colonic weight,colonic length,intestinal weight index,occult blood scores,and histological scores of mice were examined to evaluate the curative effect.The levels of memory B cells in peripheral blood of mice were measured by flow cytometry,and IL-1β,IL-6,IL-10,IL-7A,and TNF-αexpression in colonic tissue homogenates were analyzed by enzyme-linked immunosorbent assay.Western blot was used to measure the expression of Bcl-6,BLNK,Syk,and other signaling pathway related proteins.RESULTS After Cur treatment for 14 d,the body weight,colonic weight,colonic length,colonic weight index,and colonic pathological injury of mice with colitis were ameliorated.The secretion of IL-1β,IL-6,TNF-α,and IL-7A was statistically decreased,while the IL-35 and IL-10 levels were considerably increased.Activation of memory B cell subsets in colitis mice was confirmed by a remarkable reduction in the expression of IgM,IgG,IgA,FCRL5,CD103,FasL,PD-1,CD38,and CXCR3 on the surface of CD19^(+)CD27^(+)B cells,while the number of CD19^(+)CD27^(+)IL-10^(+)and CD19^(+)CD27^(+)Tim-3^(+)B cells increased significantly.In addition,Cur significantly inhibited the protein levels of Syk,p-Syk,Bcl-6,and CIN85,and increased BLNK and p-BLNK expression in colitis mice.CONCLUSION Cur could effectively alleviate DSS-induced colitis in mice by regulating memory B cells and the Bcl-6-Syk-BLNK signaling pathway.

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.

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.

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.

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) :

A Low Power SRAM/SOI Memory Cell Design

A modified four transistor （4T） self-body-bias structured SRAM/SOI memory cell is proposed. The structure is designed and its parameters are obtained by performance simulation and analysis with TSUPREM4 and MEDICI.The structure saves area and its process is simplified by using the body resistor with buried p^＋ channel beneath the nMOS gate instead of the pMOS of 6T CMOS SRAM. Furthermore, this structure can operate safely with a 0.5V supply voltage, which may be prevalent in the near future. Finally, compared to conventional 6T CMOS SRAM,this structure＇s transient responses are normal and its power dissipation is 10 times smaller.

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.

Total Ionization Dose Effects on Charge Storage Capability of Al2O3/HfO2/Al2O3-Based Charge Trapping Memory Cell

Because of the discrete charge storage mechanism, charge trapping memory（CTM） technique is a good candidate for aerospace and military missions. The total ionization dose（TID） effects on CTM cells with Al2O3/HfO2/Al2O3（AHA） high-k gate stack structure under in-situ 10 keV x-rays are studied. The C-V characteristics at different radiation doses demonstrate that charge stored in the device continues to be leaked away during the irradiation,thereby inducing the shift of flat band voltage（V（fb））. The dc memory window shows insignificant changes, suggesting the existence of good P/E ability. Furthermore, the physical mechanisms of TID induced radiation damages in AHA-based CTM are analyzed.

A fuzzy logic resource allocation and memory cell pruning based artificial immune recognition system

In order to improve the resource allocation mechanism of artificial immune recognition system(AIRS) and decrease the memory cells,a fuzzy logic resource allocation and memory cell pruning based AIRS(FPAIRS) is proposed.In FPAIRS,the fuzzy logic is determined by a parameter,thus,the optimal fuzzy logics for different problems can be located through changing the parameter value.At the same time,the memory cells of low fitness scores are pruned to improve the classifier.This classifier was compared with other classifiers on six UCI datasets classification performance.The results show that the accuracies reached by FPAIRS are higher than or comparable to the accuracies of other classifiers,and the memory cells decrease when compared with the memory cells of AIRS.The results show that the algorithm is a high-performance classifier.

Target morphology and cell memory:a model of regenerative pattern formation

Despite the growing body of work on molecular components required for regenerative repair,we still lack a deep understanding of the ability of some animal species to regenerate their appropriate complex anatomical structure following damage.A key question is how regenerating systems know when to stop growth and remodeling-what mechanisms implement recognition of correct morphology that signals a stop condition？In this work,we review two conceptual models of pattern regeneration that implement a kind of pattern memory.In the first one,all cells communicate with each other and keep the value of the total signal received from the other cells.If a part of the pattern is amputated,the signal distribution changes.The difference fromthe original signal distribution stimulates cell proliferation and leads to pattern regeneration,in effect implementing an error minimization process that uses signaling memory to achieve pattern correction.In the second model,we consider a more complex pattern organization with different cell types.Each tissue contains a central（coordinator）cell that controls the tissue and communicates with the other central cells.Each of them keeps memory about the signals received from other central cells.The values of these signals depend on the mutual cell location,and the memory allows regeneration of the structure when it is modified.The purpose of these models is to suggest possible mechanisms of pattern regeneration operating on the basis of cell memory which are compatible with diverse molecular implementation mechanisms within specific organisms.

Deer antler stem cell niche: An interesting perspective

In recent years,there has been considerable exploration into methods aimed at enhancing the regenerative capacity of transplanted and/or tissue-resident cells.Biomaterials,in particular,have garnered significant interest for their potential to serve as natural scaffolds for cells.In this editorial,we provide commentary on the study by Wang et al,in a recently published issue of World J Stem Cells,which investigates the use of a decellularized xenogeneic extracellular matrix(ECM)derived from antler stem cells for repairing osteochondral defects in rat knee joints.Our focus lies specifically on the crucial role of biological scaffolds as a strategy for augmenting stem cell potential and regenerative capabilities,thanks to the establishment of a favorable microenvironment(niche).Stem cell differen-tiation heavily depends on exposure to intrinsic properties of the ECM,including its chemical and protein composition,as well as the mechanical forces it can generate.Collectively,these physicochemical cues contribute to a bio-instructive signaling environment that offers tissue-specific guidance for achieving effective repair and regeneration.The interest in mechanobiology,often conceptualized as a form of“structural memory”,is steadily gaining more validation and momen-tum,especially in light of findings such as these.

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.

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.

Liver-spleen axis dysfunction in COVID-19

Coronavirus disease 2019(COVID-19),caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is an acute infectious disease that spreads mainly through the respiratory route.Besides interstitial pneumonia,a number of other clinical manifestations were noticed in COVID-19 patients.In particular,liver and spleen dysfunctions have been described both as complications of COVID-19 and as potential predisposing factors for severe COVID-19.Liver damage is rather common in COVID-19 patients,and it is most likely multifactorial,caused by the direct insult of SARS-CoV-2 to the liver by the cytokine storm triggered by the virus,by the use of hepatotoxic drugs,and as a consequence of hypoxia.Although generally mild,liver impairment has been found to be associated with a higher rate of intensive care unit admission.A higher mortality rate was reported among chronic liver disease patients.Instead,spleen impairment in patients with COVID-19 has been poorly described.The main anatomical changes are the architectural derangement of the B cell compartment,white pulp atrophy,and reduction or absence of lymphoid follicles,while,from a functional point of view,the IgM memory B cell pool is markedly depleted.The outcome of COVID-19 in asplenic or hyposplenic patients is yet to be defined.In this review,we will summarise the current knowledge regarding the impact of SARS-CoV-2 on the liver and spleen function,as well as the outcome of patients with a pre-existent liver disease or defective spleen function.

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.

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.