Are CD45RO^(+)and CD45RA^(-)genuine markers for bovine memory T cells?

Effective vaccination in duces memory T cells,which protect the host against pathogen re-infecti ons.Therefore,detection of memory T cells is essential for evaluating vaccine efficacy,which was originally dependent on cytokine induction assays.Currently,two isoforms of CD45 tyrosine phosphatase,CD45RO expression and CD45RA exclusion(CD45RO^(+)/CD45RA^(-)) are used extensively for detecting memory T cells in cattle.The CD45RO^(+)/CD45RA^(-) markers were first established in humans around three decades ago,and were adopted in cattle soon after.However,in the last two decades,some published data in humans have challenged the initial paradigm,and required multiple markers for identifying memoryT cells.On the contrary,memoryT cell detection in cattle still mostly relies on CD45RO^(+)/CD45RA^(-)despite some con troversial evidence.In this review,we summarized the current literature to exami ne if CD45RO^(+)/CD45RA^(-)are valid markers for detecting memoryT cells in cattle.It seems CD45RA and CD45RO(CD45RA/RO)as markers for identifyi ng bovine memoryT cells are questi on able.

Impact of T cells on hematopoietic stem and progenitor cell function:Good guys or bad guys?

When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.

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.

Memory Phenotypes of HIV-Specific CD8+ T Cell Responses Are Independent of Functional Activity as Defined by Cytokine Output

Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, the extent to which specific memory phenotypic categories of CD8+ T cells reliably represent their functional attributes remains controversial. Methods: We simultaneously assessed surface phenotype and functionality of HIV-specific CD8+ T cells by multiparametric flow cytometry, measuring five CD8+ T cell functions (CD107a, IFNγ, MIP-1β, TNFα and IL2) and phenotypic markers CCR7, CD45RA, and CD27, in parallel in 24 HIV-infected individuals. Results: Virus-specific responses were contained within all eight phenotypic categories defined using CCR7, CD45RA, and CD27. Phenotypic profiles of HIV-specific cells differed from CEF-specific cells, with HIV-specific cells having higher levels of CD45RA (p = 0.008). Interestingly a large portion of CEF and HIV-specific cells were found within previously undefined phenotypes CCR7+CD27-CD45RA+ (14.6% and 17.2%, respectively) and CCR7+CD27-CD45RA-(14.8% and 15.8%, respectively). In addition, up to 10% - 20% of responding cells were phenotypically “naive”. Additionally, memory phenotypes of cells exhibiting monofunctional and polyfunctional responses frequently differed, and failed to associate with a consistent phenotype representing functionally active cells. Conclusion: These data suggest that particularly after antigen stimulation, that surface phenotypes defined by CCR7, CD27 and CD45RA expression on antigen-specific CD8+ T cells, reflect a wide range of immunological functions, and that no single phenotype defined by memory marker expression can reliably be used to identify functional capacity.

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.

CD4+T cells memorize obesity and promote weight regain

Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.

Berberine improves central memory formation of CD8^(+)T cells:Implications for design of natural product-based vaccines

Berberine(BBR)as one of the most effective natural products has been increasingly used to treat various chronic diseases due to its immunosuppressive/tolerogenic activities.However,it is unknown if BBR can be applied without abrogating the efforts of vaccination.Here we show that priming of CD8^(+)T cells in the presence of BBR lead to improved central memory formation(Tcm)with substantially reduced effector proliferation,primarily orchestrated through activation of AMPK and Stat5.Tcm derived from vaccinated mice fed with BBR were able to adoptively transfer protective immunity to naIve recipients.Vaccination of BBR-fed mice conferred better memory protection against infection without losing immediate effector efficacy,suggesting appreciable benefits from using BBR in vaccination.Thus,our study may help to lay the groundwork for mechanistic understanding of the immunomodulatory effects of natural products and their potential use as adjuvant that allows the design of novel vaccines with more desirable properties.

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.

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.

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.

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.

Human CD4 ＋ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

The peripheral repertoire of CD4＋ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4＋ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4＋ lymphocytes activated by dendritic cells （DCs） presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells （Tmem） from primary effectors activated with mature autologous DCs plus interleukin （IL）-2 （Tmauto）, simulating the circumstances of an active immune response, or allogeneic DCs （Tmallo）. Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors （demonstrated by CD25 downregulation） particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and TmaHo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tma^o were closely related to conventional memory lymphocytes based on Erk-l/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4＋ T lymphocytes recognizing self-peptides in the setting of strong costimulation.

Functions of NKG2D in CD8^(+) T cells: an opportunity for immunotherapy

Natural killer group 2 member D(NKG2D)is a type II transmembrane receptor.NKG2D is present on NK cells in both mice and humans,whereas it is constitutively expressed on CD8+T cells in humans but only expressed upon T-cell activation in mice.NKG2D is a promiscuous receptor that recognizes stress-induced surface ligands.In NK cells,NKG2D signaling is sufficient to unleash the killing response;in CD8+T cells,this requires concurrent activation of the T-cell receptor(TCR).In this case,the function of NKG2D is to authenticate the recognition of a stressed target and enhance TCR signaling.CD28 has been established as an archetype provider of costimulation during T-cell priming.It has become apparent,however,that signals from other costimulatory receptors,such as NKG2D,are required for optimal T-cell function outside the priming phase.This review will focus on the similarities and differences between NKG2D and CD28;less well-described characteristics of NKG2D,such as the potential role of NKG2D in CD8+T-cell memory formation,cancer immunity and autoimmunity;and the opportunities for targeting NKG2D in immunotherapy.

Role of Triggering Receptor Expressed on Myeloid Cell-1 Expression in Mammalian Target of Rapamycin Modulation of CD8＋ T-cell Differentiation during the Immune Response to Invasive Pulmonary Aspergillosis

Background： Triggering receptor expressed on myeloid cell- 1 （TREM- 1） may play a vital role in mammalian target ofrapamycin （mTOR） modulation ofCD8＋ T-cell differentiation through the transcription factors T-box expressed in T-cells and eomesodermin during the immune response to invasive pulmonary aspergillosis （IPA）. This study aimed to investigate whether the roTOR signaling pathway modulates the proliferation and differentiation of CD8＋ T-cells during the immune response to I PA and the role TREM-1 plays in this process. Methods： Cyclophosphamide （CTX） was injected intraperitoneally, and Asl？e;gillus.[mnigams spore suspension was inoculated intranasally to establish the immunosuppressed IPA mouse model. After inoculation, rapamycin （2 mg-kg ·d -1） or interleukin （IL）-12 （5 μg/kg every other day） was given for 7 days. The number of CD8＋ effector memory T-cells （Tern）, expression of interferon （IFN）-y, roTOR, and ribosomal protein $6 kinase （S6K）, and the levels of IL-6, IL- 10, galactomannan （GM）, and soluble TREM- 1 （sTREM-I） were measured. Results： Viable A. fumigatus was cultured from the lung tissue of the inoculated mice. Histological examination indicated greater inflammation, hemorrhage, and lung tissue injury in both IPA and CTX ＋ IPA mice groups. The expression of mTOR and S6K was significantly increased in the CTX ＋ IPA ＋ I L- 12 group compared with the control, I PA （P = 0.01 ; P - 0.001 ）, and CTX ＋ 1PA （P = 0.034; P = 0.032） groups, but significantly decreased in the CTX ＋ IPA ＋ RAPA group （P 〈 0.001 ）. Compared with the CTX ＋ IPA group, the proportion of Tern, expression of IFN-y, and the level ofsTREM-I were significantly higher after IL-12 treatment （P = 0.024, P = 0.032, and P = 0.017, respectively）, and the opposite results were observed when the roTOR pathway was blocked by rapamycin （P 〈 0.001）. Compared with the CTX ＋ I PA and CTX ＋ I PA ＋ RAPA groups, IL-12 treatment increased IL-6 and downregulated IL- 10 as well as G M, which strengthened the immune response to the IPA infection. Conclusions： mTOR modulates CD8＋ T-cell differentiation during the immune response to IPA. TREM-1 may play a vital role in signal transduction between mTOR and the downstream immune response.

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.

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.

The Hematopoietic and Immunomodulatory Effect of rhIL-12 for Liver Cancer

Purpose: To explore the effect of rhIL-12 on the number of the blood cells and CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells in liver cancer patients following radiation therapy. Methods: We selected forty liver cancer patients who carried out by cyber knife (the patients were given 5 Gy every time for 5 times continuously) to observe the size of the tumor. After thirty hours, rhIL-12 was injected into the liver cancer patients via subcutaneous at the concentration of 50 ng/kg, 100 ng/kg, 200 ng/kg and 300 ng/kg in different patients, respectively. And there were ten patients in the four groups, respectively. The twenty patients who were selected from the hospital without rhIL-12 treatment were used as controls. All the blood cells were collected from different groups on day 0, hour 12, day 7, day 14, day 21 and day 28 after rhIL-12 treatment, respectively. The full number of blood cells in every group was analyzed by ELISA. The number of CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells were detected by Flow Cytometry. After one month with rhIL-12 treatment, ECOG and WHO were used to evaluate the prognosis of liver cancer. Results: In present study, we found that the number of blood cells was significantly decreased on day 0 - day 3, while recovered from day 7 - day 14 and down-regulated on day 21 after rhIL-12 treatment. The number of CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells was elevated with any concentration of rhIL-12. Furthermore, results showed that number of white blood cells was obviously higher than in patients without rhIL-12 treatment (P < 0.05). However, there was no significant difference of erythrocyte and platelet, between groups treated with rhIL-12 and control groups. In addition, the immune cells including CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells were reduced on day 0 - day 3, recovered from day 7, and then decreased from day 21 in rhIL-12 treatment groups related to control groups (P < 0.05). Furthermore, studies showed that five patients developed symptoms of fever, bilirubin increased and liver dysfunction with the dose of 300 ng/kg. So we found that the safe and well-tolerated human dose of 200 ng/kg is within this efficacious range based on exposure parameters through the research. Higher ECOG and WHO scores were observed in rhIL-12 treatment groups compared to control groups (P = 0.025, P = 0.044, respectively). Conclusion: Our results suggested that rhIL-12 could recover the liver cancer induced aberrant blood cell number and CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells , which may be an effective method to alleviate the progress of liver cancer and played an important role in treating liver cancer.

Mettl3依赖的m^(6)A甲基化调控CD8^(+)T细胞效应分化和记忆形成

Efficient immune responses rely on the proper differentiation of CD8^(+)T cells into effector and memory cells.Here,we show a critical requirement of N^6-Methyladenosine(m^(6)A)methyltransferase Mettl3 during CD8^(+)T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8^(+)T cells impairs effector expansion and terminal differentiation in an m^(6)A-dependent manner,subsequently affecting memory formation and the secondary response of CD8^(+)T cells.Our combined RNA-seq and m^(6)AmiCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effector differentiation of CD8^(+)T cells.Moreover,ectopic expression of T-bet partially restores the defects in CD8^(+)T cell differentiation in the absence of Mettl3.Thus,our study highlights the role of Mettl3 in regulating multiple target genes in an m^(6)A-dependent manner and underscores the importance of m^(6)A modification during CD8^(+)T cell response.

Regulation of CD8^(+)T memory and exhaustion by the mTOR signals

CD8^(+)T cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral immunity.Naïve CD8^(+)T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial infection.Simultaneously,a fraction of these cells become long-lived memory CD8^(+)T cells that combat future infections.Notably,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute vs.chronic immunization)or fluctuations in host metabolic,inflammatory,or aging factors.Therefore,many T cells may be lost or become exhausted and no longer functional.Complicated intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this process.Therefore,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular immunity.In this review,we focus on mammalian target of rapamycin(mTOR),particularly signaling mediated by mTOR complex(mTORC)2 in memory and exhausted CD8^(+)T cells at the molecular level.

喉咽癌树突状细胞表型抗原表达

目的对喉咽癌中树突状细胞(Dendriticcells,DCs)的表型抗原的表达进行研究,探讨DC表型抗原的表达与喉咽癌各临床因素尤其是转移和预后的关系。方法对45例喉咽癌标本,用EnvisionHIS的方法检测DC的表型抗原S-100、CD1a、CD83的表达,并观察CD45RO+T细胞与DC的关系。结果S-100+DCs在高分化组以及生存组中的数目明显多于中低分化组及死亡组,具有显著性差异。CD83+DCs的表达与喉咽癌的分化程度、远处转移、生存以及是否复发有关,差异具有显著性;CD83+DCs在癌巢中的数目较癌旁中的少,差异具有显著性。CD1a+DCs的表达与喉咽癌的各临床因素间未发现明显相关性。CD45RO+T细胞主要分布在CD83+DCs的周围。结论表达不同表型抗原的DC具有不同的功能,CD83+DCs被认为是成熟DC分布在癌旁与其激活T细胞的抗原提呈功能有关,对于肿瘤免疫防御机制的建立起着重要作用。DC在喉咽癌中的浸润程度及表型抗原的表达情况是反映宿主肿瘤免疫状况的重要指标,也是预测喉咽癌转移和预后的一项重要指标。