Ability of CD8(+) T cell anti-feline immunodeficiency virus activity correlated with peripheral CD4(+) T cell counts and plasma viremia

In the host defense mechanism against feline immunodeficiency virus (FIV) infection, CD8(+) T cells specifically attack virus-infected cells and suppress the replication of the virus in a non-cytolytic manner by secreting soluble factors. In this study, we measured CD8(+) T cell anti-FIV activity in 30 FIV-infected cats. We investigated its relationship with the number of peripheral blood lymphocytes, particularly the CD4(+) T cell and CD8(+) T cell counts, and the relationship between anti-FIV activity and the number of T cells of CD8alpha(+)beta(lo) and CD8alpha(+)beta(-) phenotypes. A clearly significant correlation was observed between anti-FIV activity and the number of CD4(+) T cells. A weaker anti-FIV activity was associated with a greater decrease in the number of CD4(+) T cells. However, there was no significant correlation between anti-FIV activity and the number of B or CD8(+) T cells. Compared with SPF cats, FIV-infected cats had significantly higher CD8alpha(+)beta(lo) T cell and CD8alpha(+)beta(-) T cell counts, but, no significant correlation was observed between these cell counts and anti-FIV activity. This anti-FIV activity significantly correlated with plasma viremia, which was detected in cats with a weak anti-FIV activity. These results suggest that the anti-FIV activity of CD8(+) T cells plays an important role in plasma viremia and the maintenance of CD4(+) T cells in the body. It is unlikely that CD8alpha(+)beta(lo) or CD8alpha(+)beta(-) T cells appearing after FIV infection represent a phenotype of CD8(+) cells with anti-FIV activity.     

The role of CD4 T cell help for CD8 CTL activation

CD4 T cells play an important role in the initiation and persistence of CD8 T cells responses. In this review, we report on and evaluate the mechanisms by which CD4 T cells contribute to activation of CD8 T cells and the signal pathways of the down-streaming events after CD4 T cell help.     

Splenic dendritic cell subsets prime and boost CD8 T cells and are involved in the generation of effector CD8 T cells

The ability of the dendritic cell (DC) subsets, CD8alpha+ and CD8alpha- DCs, to initiate a CD8 T cell response or to activate memory CD8 T cells and generate effector CD8 T cells has been controversial. In this study, we analyse the capacity of splenic DC subsets to induce CD8 T cell responses to a CD8 T cell epitope (pb9) of a malaria antigen. The administration of peptide-pulsed CD8alpha- or CD8alpha+ DCs primes and boosts a primed CD8 T cell response against the malaria epitope. In vitro, depletion of CD11c(+) DCs from mouse splenocytes, immunised with recombinant vaccinia virus Ankara (MVA) expressing pb9 epitope, significantly reduced the generation of pb9-specific IFNgamma producing effector CD8 T cells, indicating that splenic DCs are involved in the development of pb9-specific IFNgamma producing effector cells. Taken together, this result shows that both DC subsets have the ability to prime and boost CD8 T cell responses and are involved in the activation of memory CD8 T cells.     

HIV-specific CD8+ T cell responses to HXB2 Gag and Nef peptide pools in Chinese HIV/AIDS patients

HXB2 is primarily used as a template strain in developing HIV vaccines in Europe and the US. However,it is not yet known whether the strain can induce strong HIV-specific CD8+ T cell responses in Chinese HIV/AIDS patients. In the present study,two groups of subjects were investigated:9 AIDS patients and 7 long-term nonprogressors (LTNPs). HIV-specific CD8+ T cell responses were examined in all patients through the ELISPOT assay. CD4+ T cell counts,CD8+ T cell counts,viral load and HIV subtype of each patien...     

Coreceptor CD8-driven modulation of T cell antigen receptor specificity

The CD8 coreceptor modulates the interaction between the T cell antigen receptor (TCR) and peptide-major histocompatibility class I (pMHCI). We present evidence that CD8 not only modifies the affinity of cognate TCR/pMHCI binding by altering both the association rate and the dissociation rate of the TCR/pMHCI interaction, but modulates the sensitivity (triggering threshold) of the TCR as well, by recruiting TCR/pMHCI complexes to membrane microdomains at a rate which depends on the affinity of MHCI/CD8 binding. Mathematical analysis of these modulatory effects indicates that a T cell can alter its functional avidity for its agonists by regulating CD8 expression, and can rearrange the relative potencies of each of its potential agonists. Thus we propose that a T cell can specifically increase its functional avidity for one agonist, while decreasing its functional avidity for other potential ligands. This focussing mechanism means that TCR degeneracy is inherently dynamic, allowing each TCR clonotype to have a wide range of agonists while avoiding autorecognition. The functional diversity of the TCR repertoire would therefore be greatly augmented by coreceptor-mediated ligand focussing.     

Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

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Modulation of MOG 37-50-specific CD8+ T cell activation and expansion by CD43

Several recent reports have described an effector role for CD8(+) T cells during EAE. We have previously demonstrated reduced disease incidence and severity in CD43(-/-) mice following MOG immunization, and attributed this attenuation in disease progression to the effects of CD43 deficiency on CD4+ T cells. Here, we extend those studies to examine the effects of the loss of CD43 on MOG-specific CD8+ T cells. A reduced frequency of MOG-specific CD8+ T cells following immunization was observed in CD43(-/-) mice relative to wild-type controls, as demonstrated by intracellular cytokine and MHC tetramer staining. In addition, adoptive transfer of CD8+ MOG 35-55-primed LN cells from CD43(-/-) mice resulted in significantly attenuated EAE induction as compared to recipients of wild-type CD8+ MOG-primed cells. Analysis of intracellular signaling intermediates revealed a deficiency in the ability of MOG-specific CD8+ T cells to phosphorylate ERK in response to antigen. These results characterize an important role for CD43 during the activation and expansion of autoreactive MOG-specific CD8+ T cells.     

4-1BB costimulation enhances HSV-1-specific CD8+ T cell responses by the induction of CD11c+CD8+ T cells

Since 4-1BB plays a predominant role in CD8+ T cell responses, we investigated the effects of 4-1BB triggering on the primary and memory CD8+ T responses to HSV-1 infection. 4-1BB was detected on 10-15% of CD4+ and CD8+ T cells following the infection. 4-1BB-positive T cells were in the proliferative mode and showed the enhanced expression of anti-apoptotic proteins. Agonistic anti-4-1BB treatment exerted preferential expansion of CD8+ T cells and gB/H-2Kb-positive CD8+ T cells, and enhanced cytotoxicity against HSV-1 that was mainly mediated by CD11c+CD8+ T cells. CD11c+CD8+ T cells were re-expanded following re-challenge with HSV-1 at post-infection day 50, indicating that CD11c+CD8+ phenotype was maintained in memory CD8+ T cell pool. Our studies demonstrated that 4-1BB stimulation enhanced both primary and memory anti-HSV-1 CD8+ T cell responses, which was mediated by a massive expansion of antigen-specific CD11c+CD8+ T cells.     

Identification of SIV Nef CD8 T cell epitopes restricted by a MHC class I haplotype associated with lower viral loads in a macaque AIDS model

Virus-specific CD8⁺ T-cell responses are crucial for the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. Multiple studies on HIV-infected individuals and SIV-infected macaques have indicated association of several major histocompatibility complex class I (MHC-I) genotypes with lower viral loads and delayed AIDS progression. Understanding of the viral control mechanism associated with these MHC-I genotypes would contribute to the development of intervention strategy for HIV control. We have previously reported a rhesus MHC-I haplotype, 90-120-Ia, associated with lower viral loads after SIVmac239 infection. Gag_206–216 and Gag_241–249 epitope-specific CD8⁺ T-cell responses have been shown to play a central role in the reduction of viral loads, whereas the effect of Nef-specific CD8⁺ T-cell responses induced in all the 90-120-Ia⁺ macaques on SIV replication remains unknown. Here, we identified three CD8⁺ T-cell epitopes, Nef_9–19, Nef_89–97, and Nef_193–203, associated with 90-120-Ia. Nef_9–19 and Nef_193–203 epitope-specific CD8⁺ T-cell responses frequently selected for mutations resulting in viral escape from recognition by these CD8⁺ T cells, indicating that these CD8⁺ T cells exert strong suppressive pressure on SIV replication. Results would be useful for elucidation of the viral control mechanism associated with 90-120-Ia.     

Cross-primed CD8+ cytotoxic T cells induce severe Helicobacter-associated gastritis in the absence of CD4+ T cells

BACKGROUND: Although previous studies have reported important roles of CD4(+) type 1-helper T cells and regulatory T cells in Helicobacter-associated gastritis, the significance of CD8(+) cytotoxic T cells remains unknown. To study the roles of CD8(+) T cells, we examined the immune response in the gastric mucosa of Helicobacter felis-infected major histocompatibility complex (MHC) class II-deficient (II(-/-)) mice, which lack CD4(+) T cells. MATERIALS AND METHODS: Stomachs from H. felis-infected wild-type and infected MHC II(-/-) mice were examined histologically and immunohistochemically. Gastric acidity and serum levels of anti-H. felis antibodies were measured. The expression of pro-inflammatory and anti-inflammatory cytokine, Fas-ligand, perforin, and Foxp3 genes in the gastric mucosa was investigated. RESULTS: H. felis-infected MHC II(-/-) mice developed severe gastritis, accompanied by marked infiltration of CD8(+) cells. At 1 and 2 months after inoculation, mucosal inflammation and atrophy were more severe in MHC II(-/-) mice, although gastritis had reached similar advanced stages at 3 months after inoculation. There was little infiltration of CD4(+) cells, and no Foxp3-positive cells were detected in the gastric mucosa of the infected MHC II(-/-) mice. The expression of the interleukin-1beta and Fas-ligand genes was up regulated, but that of Foxp3 was down regulated in the infected MHC II(-/-) mice. Serum levels of anti-H. felis antibodies were lower in the infected MHC II(-/-) mice, despite severe gastritis. CONCLUSIONS: The present study suggests that cross-primed CD8(+) cytotoxic T cells can induce severe H.-associated gastritis in the absence of CD4(+) helper T cells and that Foxp3-positive cells may have an important role in the control of gastric inflammation.     

T cell receptor repertoire of CD4+ and CD8+ T cell subsets in the allogeneic bone marrow transplant recipient

Allogeneic bone marrow transplantation (BMT) has become a therapy of choice for the treatment of certain malignancies and hematopoietic disorders. However, immunodeficiencies following BMT continue to cause significant morbidity and mortality. We have compared the T cell receptor (TCR) repertoire of BMT patients and healthy control individuals by staining peripheral blood mononuclear cells with fluorochrome-labeled TCR-specific antibodies. Several patients exhibited a biased pattern of TCR expression atypical of the healthy controls, yet no particular TCR bias characterized all patients. For example, we found that 2%–8% of T cell from healthy individuals expressed the V19 TCR. One BMT patient exhibited V19 expression on more than 60% of peripheral T cells, while additional patients expressed V19 on less than 1% of T cells. The patients with the most extreme skewing of TCR types suffered from graft-versus-host disease. The causes of skewed TCR V expression patterns in BMT patients are not fully understood, yet some researchers have suggested that an oligoclonal expansion of CD8⁺ T cell populations may be largely responsible. To test this hypothesis, we examined the TCR V repertoire of CD4⁺ and CD8⁺ T cell populations. We found that biased V expression characterized both CD4⁺ and CD8⁺ T cell populations, sometimes within a single individual. Thus, therapies directed toward CD8⁺ T cells alone may not fully correct repertoire abnormalities following BMT.     

Autophagy-mediated antigen processing in CD4 T cell tolerance and immunity

Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to deliver antigens for presentation on major histocompatibility complex (MHC) class II. Autophagy-mediated antigen processing in thymic epithelial cells has been suggested to be involved in the generation of a self-MHC restricted and self-tolerant CD4⁺ T cell repertoire. Furthermore, there is accumulating evidence that the up-regulation of autophagy by pattern-recognition receptor signaling represents an innate defense mechanism against intracellular pathogens. Thus, through linking pathogen breakdown with the presentation of pathogen-derived autophagy substrates on MHC class II, autophagy serves a dual function at the interface of the innate and the adaptive immune response.     

CD8~+CD122~+T细胞在脑缺血过程中作用的研究

目的:探讨CD8+CD122+T细胞在脑缺血过程中的作用及其机制。方法:线栓法建立小鼠大脑中动脉栓塞模型(MCAO);激光共聚焦显微镜检测小鼠脑缺血组织中CD8+CD122+T细胞浸润情况;流式细胞仪检测脑缺血组织中CD8+CD122+T细胞/CD3+T细胞的比例及脾和胸腺中CD8+CD122+T细胞数量变化;RT-PCR方法检测CD8+CD122+T细胞对氧糖剥夺(Oxygen-glucose deprivation,OGD)条件下星形胶质细胞表达TNF-α,IL-1β,IFN-γ的影响。结果:各时间点脑缺血组织中均有CD8+CD122+T细胞浸润,且随脑缺血时间延长,缺血侧脑组织中CD8+CD122+T细胞/CD3+T细胞比例逐渐增加,5 d和7 d组差异显著,与非缺血侧相比,P5d0.05,P7d0.05;MCAO小鼠脾及胸腺中CD8+CD122+T细胞呈现先增高后降低的趋势。星形胶质细胞经OGD处理后,与对照组相比,IFN-γ、TNF-α、IL-1β表达显著增高,PIFN-γ0.01、PTNF-α0.001、PIL-1β0.01;CD122-blocked组与CD8+组相比,IFN-γ、TNF-α、IL-1β表达明显增高,PIFN-γ0.05、PTNF-α0.05、PIL-1β0.01;CD8+组与HBSS组相比,IFN-γ表达降低,P0.05;IL-1β表达有降低的趋势。结论:CD8+CD122+T细胞在脑缺血过程中发挥保护性作用,其保护作用通过CD122抑制星形胶质细胞TNF-α,IL-1β,IFN-γ炎症因子表达实现的。     

IL-15扩增的OT-Ⅰ细胞持续抑制小鼠黑色素瘤生长

过继免疫治疗(adoptive cell transfer,ACT)是肿瘤治疗中一种有效的免疫治疗手段,但是在没有化疗或者放疗等辅助治疗手段时,过继免疫治疗缓解肿瘤生长的效果非常短暂.为了探索一种更为有效的过继免疫治疗手段,我们使用白介素15(IL-15)体外扩增OT-ⅠCD8 T细胞,使其分化成为中央记忆性T细胞(central memory T cells,TCM),并将其过继转移至携带B16-OVA肿瘤的小鼠中.我们发现,与IL-2体外扩增的CD8 T细胞(effector T cells,TEFF)相比,TCM对肿瘤的生长具有长时间的缓解作用,而IL-2分化的TEFFs治疗肿瘤在短暂的缓解后反弹性生长.进一步的研究发现,TCM治疗的小鼠脾脏内肿瘤抗原特异性的T细胞数量和比例明显高于TEFF组,并且RT-PCR分析表明TCM治疗的小鼠肿瘤内细胞高表达MHCⅠ类分子.这些现象提示了抗原提呈对过继细胞转移治疗的效果具有重要作用.我们的研究对于发展更为有效的肿瘤免疫治疗具有提示意义.     

Impaired antigen-induced CD8+ T cell clonal expansion in aging is due to defects in antigen presenting cell function

CD8+ T cell activation depends on interaction with antigen-presenting cells (APCs) and this interaction leads to the expansion of T cells with the capacity to control infection. Using professional APCs, we demonstrate that with age, the duration of APC-T cell contact time required to achieve clonal expansion increases. Na?ve CD8+ T cells from aged mice showed no defect in antigen-induced proliferation when stimulated with APC from young mice. In contrast, CD8+ T cells from young mice exhibited reduced clonal expansion and secreted significantly lower amounts of IFN-gamma when stimulated by APCs from aged mice. The aged APCs were defective in costimulatory molecule expression and cytokine and chemokine secretion. These data indicate that defects in APC function lead to poor T cell clonal expansion and function in aging.     

Heterologous CD8 T cell immune response to HSV induced by toll like receptor ligands

A memory response is established following primary antigen exposure that stays more or less constant. It appears to adopt a set-point in magnitude but upon re-exposure the response is quicker and better and there is an upward shift in memory frequency that varies with individuals based on the exposure pattern to other microbes or its components. Our investigations were designed to test such differences of non-specific stimulation by PAMPs in lowering the threshold of activation. Neonatal mice were pre-exposed to TLR-ligands intermittently and later analyzed for its resilience to challenge with virus during adult-life. Secondly, adult mice with pre-existing memory to virus were exposed to various TLR-ligands and analyzed for their quality of memory response. The TLR-ligands exposed animals were better responders to a new agent exposure compared to the animals kept in sterile surroundings. Moreover, immune memory recall and the viral specific CD8⁺ T cells response with TLR-ligands were comparable to the recall response with the cognate antigen. The results provide insights into the role of hyper-sanitized environment versus PAMPs mediated signaling in adaptive immunity and long-term immune memory.     

Traffic of proteins and peptides across membranes for immunosurveillance by CD8(+) T lymphocytes: a topological challenge

Cytotoxic CD8(+) T lymphocytes kill infected cells that display major histocompatibility complex (MHC) class I molecules presenting peptides processed from pathogen proteins. In general, the peptides are proteolytically processed from newly made endogenous antigens in the cytosol and require translocation to the endoplasmic reticulum (ER) for MHC class I loading. This last task is performed by the transporters associated with antigen processing (TAP). Sampling of suspicious pathogen-derived proteins reaches beyond the cytosol, and MHC class I loading can occur in other secretory or endosomal compartments besides the ER. Peptides processed from exogenous antigens can also be presented by MHC class I molecules to CD8(+) T lymphocytes, in this case requiring delivery from the extracellular medium to the processing and MHC class I loading compartments. The endogenous or exogenous antigen can be processed before or after its transport to the site of MHC class I loading. Therefore, mechanisms that allow the full-length protein or processed peptides to cross several subcellular membranes are essential. This review deals with the different intracellular pathways that allow the traffic of antigens to compartments proficient in processing and loading of MHC class I molecules for presentation to CD8(+) T lymphocytes and highlights the need to molecularly identify the transporters involved.     

PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion

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CD8+T细胞在多发性硬化中的致病性作用

多发性硬化是T细胞介导的自身免疫性疾病。先前对它的研究大多集中在CD4 T细胞的致病和调节性作用上,但是,近几年来越来越多的证据表明CD8 T细胞也参与多发性硬化的病理损伤过程。 CD8 T细胞存在于MS病灶部位,髓鞘抗原特异性CD8 T细胞也从MS患者的血液和脑脊液中分离得到,CD8 T细胞通过直接杀伤或释放细胞因子和趋化因子等间接参与MS的病理过程。本文就近几年关于CD8 T细胞在多发性硬化中的致病性作用的研究进展予以介绍。