Peptide-specific activation of cytolytic CD4+ T lymphocytes against tumor cells bearing mutated epitopes of K-ras p21

Alterations in the ras p21 protein have been associated with both rodent and human neoplasia. Thus, mutated ras p21 proteins may bear unique antigenic epitopes for immune recognition, such as by T cells, which have been implicated in host antitumor activity. Synthetic peptides that mimic segments of mutated ras p21 have been reported to be immunogenic in mice in vivo, although detailed functional analyses remains undefined. Here, in a murine model, we explored and characterized distinct effector properties of host-derived T lymphocytes reactive to mutated ras peptides, which was consistent with the CD4⁺ T helper type 1 (T_h1) subset. BALB/c mice (H-2^d) were immunized with a purified peptide, 13 amino acids in length, containing the substitution of Gly (G12) to Val (V12) at position 12, which is commonly found in human carcinomas. An αβ T cell receptor-positive, CD3⁺, CD4⁺, CD8^? T cell line was established, which expressed peptide-specific proliferation. Cytokine assays revealed the production of interleukin-2, interferon-γ, tumor necrosis factor and granulocytemacrophage colony-stimulating factor. Moreover, antigen-specific cytotoxicity was demonstrable against: (1) Ia^d-bearing A20 tumor cells incubated with exogenously bound V12 peptide; and (2) A20 tumor cells transduced with the K-ras p21 oncogene encoding the corresponding point mutation. CD4⁺-mediated cytotoxicity was major histocompatibility complex (MHC) class II-restricted, as revealed by the absence of lysis against MHC class II^? P815 targets, inhibition of A20 lysis with anti-Ia^d monoclonal antibodies, and induction of lysis against L cell targets transfected with EαAβ^d. Independent isolation of a second CD4⁺ V12 line revealed a very similar cytolytic and MHC class II-restricted profile. Overall, these data demonstrated that peptide immunization produced a CD4⁺ T_h1 response that specifically recognized tumor cells expressing endogenous activated K-ras epitopes, which may have implications for the development of peptide-based active immunotherapies.     

CD3-induced apoptosis of CD4+CD8+ thymocytes in the absence of clonotypic T cell antigen receptor

Clonal selection of T cells mediated through the T cell antigen receptor (TCR) mostly occurs at the CD4⁺CD8⁺ double positive thymocyte stage. Immature CD4⁺CD8⁺ thymocytes expressing self-reactive TCR are induced to die upon clonotypic engagement of TCR by self antigens. CD3 engagement by antibody of the surface TCR-CD3 complex is known to induce apoptosis of CD4⁺CD8⁺ thymocytes, a process that is generally thought to represent antigen-induced negative selection in the thymus. The present study shows that the CD3-induced apoptosis of CD4⁺CD8⁺ thymocytes can occur even in TCRα^? mutant mice which do not express the TCRαβ/CD3 antigen receptor. Anti-CD3 antibody induces death of CD4⁺CD8⁺ thymocytes in TCRα^? mice either in cell cultures or upon administration in vivo. Interestingly, most surface CD3 chains expressed on CD4⁺CD8⁺ thymocytes from TCRα^? mice are not associated with clonotypic TCR chains, including TCRβ. Thus, apoptosis of CD4⁺CD8⁺ thymocytes appear to be induced through the CD3 complex even in the absence of clonotypic antigen receptor chains. These results shed light on previously unknown functions of the clonotype-independent CD3 complex expressed on CD4⁺CD8⁺ thymocytes, and suggest its function as an apoptotic receptor inducing elimination of developing thymocytes.     

CD40 ligand-positive CD8+ T cell clones allow B cell growth and differentiation

A fraction of activated CD8⁺ T cells expresses CD40 ligand (CD40L), a molecule that plays a key role in T cell-dependent B cell stimulation. CD8⁺ T cell clones were examined for CD40L expression and for their capacity to allow the growth and differentiation of B cells, upon activation with immobilized anti-CD3. According to CD40L expression, CD8⁺ clones could be grouped into three subsets. CD8⁺ T cell clones expressing high levels of CD40L (≥80% CD40L⁺ cells) were equivalent to CD4⁺ T cell clones with regard to induction of tonsil B cell proliferation and immunoglobulin (Ig) production, provided the combination of interleukin (IL)-2 and IL-10 was added to cultures. CD8⁺ T cell clones, with intermediate levels of CD40L expression (10 to 30% CD40L⁺ cells), also stimulated B cell proliferation and Ig secretion with IL-2 and IL-10. B cell responses induced by these CD8⁺ T cell clones were neutralized by blocking monoclonal antibodies specific for either CD40L or CD40. By contrast, CD40L^?? T cell clones (?5 % CD40L⁺ cells), only induced marginal B cell responses even with IL-2 and IL-10. All three clone types were able to activate B cells as shown by up-regulation of CD25, CD80 and CD86 expression. A neutralizing anti-CD40L antibody indicated that T cell-dependent B cell activation was only partly dependent on CD40-CD40L interaction. These CD40L^?? clones had no inhibitory effects on B cell proliferation induced by CD40L-expressing CD8⁺ T cell clones. Taken together, these results indicate that CD8⁺ T cells can induce B cell growth and differentiation in a CD40L-CD40-dependent fashion.     

B7-1-dependent co-stimulation results in qualitatively and quantitatively different responses by CD4+ and CD8+ T cells

To characterize better the co-stimulatory activity of native B7-1 in the absence of other receptor/ligand interactions that might contribute to the response, B7-1 was purified by monoclonal antibody (mAb) affinity chromatography. Immobilization of purified B7-1 with anti-T cell receptor (TCR) mAb on cell-sized latex microspheres provided an effective stimulus for activation of both CD4⁺ and CD8⁺ T cells as measured by proliferation, development of effector function, and changes in motility and adhesion. The CD4⁺ T cell response was prolonged and resulted in efficient interleukin-2 production and clonal expansion. In contrast, CD8⁺ responses were transient. Proliferation and clonal expansion peaked on days 3 and 4, coincident with maximal expression of lytic effector function, and the cells then died. These results demonstrate that B7-1 mediated co-stimulation is sufficient for the induction of effector function in both helper and cytotoxic T cell precursors, but suggest that B7-1 co-stimulation is not sufficient to sustain helper-independent CD8⁺ CTL responses. When the dose responses of CD4⁺ and CD8⁺ T cells to B7-1 were compared, CD8⁺ T cells were found to require higher densities of B7-1 to attain an equivalent level of activation, suggesting that the level of expression of B7-1 by APC may influence the development of helper or CTL responses. Finally, in contrast to results obtained by others with B7-1 transfectants, purified B7-1 did not provide co-stimulation when presented on a surface separate from the TCR stimulus.     

慢性乙型肝炎患者CD4~+和CD8~+T细胞亚群的研究

目的:比较不同感染状态慢性乙型肝炎(CHB)患者外周血CD4+和CD8+T细胞亚群的差异。方法:收集CHB患者78例,根据感染状态分为乙型肝炎e抗原(HBeAg)阳性且肝功能正常、HBeAg阳性且肝功能异常和HBeAg阴性3组。13例健康志愿者(正常对照组)来自曙光医院体检中心。应用流式细胞术(FCM)检测不同感染状态CHB患者外周血中CD4+CD25+、CD8+CD28-、CD4+CD95+、CD8+CD95+细胞亚群的分布情况,并对各亚群分布情况与HBeAg和HBVD-NA水平的相关性进行分析。结果:与正常对照组相比,HBeAg(+)肝功能正常组的CD4+CD25+/CD4+和CD4+CD95+/CD4+明显升高(P<0.01,P<0.05),3个感染组CD8+CD28-/CD8+值均明显升高(P<0.01);与HBeAg(+)肝功能正常组相比,HBeAg(+)肝功能异常组和HBeAg(-)组的CD4+CD25+/CD4+明显降低(P<0.01),HBeAg(-)组CD8+CD95+/CD8+明显降低(P<0.05),HBeAg(+)肝功能异常组的CD8+CD95+/CD8+明显降低(P<0.01)。CD4+CD25+/CD4+,CD4+CD95+/CD4+与HBVDNA呈正相关(P<0.01,P<0.05),CD8+CD28-/CD8+与HBVDNA和HBeAg均呈正相关(P<0.01)。结论:CHB患者外周血中CD4+CD25+、CD8+CD28-T、CD4+CD95+细胞表达频率增加,可能对慢性乙肝病毒感染过程中的免疫耐受起一定作用。     

Circulating CD4+CD8+ T lymphocytes in patients with Kawasaki disease

We serially monitored cell surface antigen expression on mononuclear cells in peripheral blood isolated from patients with Kawasaki disease (KD), and found, for the first time, that a markedly increased number of CD4⁺CD8⁺ T lymphocytes was present in some of the patients (11 of the 24 cases). The cases of five of these 11 patients were complicated with coronary artery lesion (CAL); the 13 patients with normal numbers of CD4⁺CD8⁺ T lymphocytes did not have CAL. The patients' age, sex and grade of systemic inflammation evaluated by peripheral leucocyte count and serum C-reactive protein levels were not correlated to the number of CD4⁺CD8⁺ T lymphocytes. Other cell surface antigen characteristics of the CD4⁺CD8⁺ T lymphocytes included CD3⁺, CD45RA⁺, CD45RO⁺, CD16^?, and HLA-DR⁺. These results indicate that the surface antigen characteristics of the KD peripheral blood examined were the same as those of Epstein–Barr virus infection without CD45RA⁺. These findings provide useful information for the analysis of the pathogenesis of KD.     

癌灶CD4~+CD25~+和CD8~+ T细胞亚群与卵巢浆液性癌患者生存期相关

检测卵巢浆液性癌患者癌组织中CD4+CD25+及CD8+T细胞的数目,探讨其两种T细胞介导的免疫功能对疾病发展及预后的影响。免疫组织化学双标及单标的染色方法检测41例卵巢浆液性癌患者手术切除癌组织标本中CD4+CD25+和CD8+T细胞的数目。结果显示,癌灶中CD4+CD25+T淋巴细胞为(19.95±11.50)个/10HPF,CD8+T淋巴细胞为(43.46±16.69)个/10HPF。生存分析发现高CD4+CD25+T细胞组患者总生存期较低CD4+CD25+T细胞组缩短,差异有显著性(P<0.05);而高CD8+T细胞组患者总生存期与低CD8+T细胞组相比延长,且差异有显著性(P<0.05),此外两种T细胞数目与患者年龄、病理分级、临床分期、腹水细胞学及淋巴结转移等临床病理因素均无关(P>0.05)。结果表明,卵巢浆液性癌中高CD4+CD25+T细胞提示患者预后不良,可能与CD4+CD25+T细胞介导的免疫抑制导致肿瘤免疫逃逸有关;癌组织中高CD8+T细胞提示患者预后较好,两种T细胞对卵巢浆液性癌预后的评估有重要的价值,同时可以通过阻断CD4+CD25+T细胞的免疫抑制作用改善卵巢浆液性癌患者的预后,为卵巢癌治疗提供靶目标。     

Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia

Chronic sinopulmonary infections that are associated with immunodeficiency are one of the leading causes of death in the multi-systemic disease ataxia telangiectasia (AT). Immunological investigations of AT patients revealed a broad spectrum of defects in the humoral and the cellular immune system. Based on their important role in host defence the aim of our study was an extensive analysis of cell distribution and function of CD4+ and CD8+ T lymphocytes and NK cells. We found that naive (CD45RA+) CD4+ lymphocytes, as well as CD8+/CD45RA+ lymphocytes, are decreased, whereas NK cells (CD3-/CD16+CD56+) are significantly elevated in AT patients. In our culture system proliferation and cytokine production was normal in purified memory (CD45RO+) lymphocytes after stimulation with phorbol-12,13-dibutyrate (PBu2) and after PHA activation, indicating that differences in proliferation and cytokine production are due solely to reduced numbers of CD45RA+ lymphocytes. However, activation, and especially intracellular interferon production of AT lymphocytes, seem to follow different kinetics compared to controls. In contrast to polyclonal activation, stimulation via the T cell receptor results consistently in a reduced immune response. Taken together, our results suggest that deficiency of immunocompetent cells and an intrinsic immune activation defect are responsible for the immunodeficiency in AT.     

Antigen-specific CD8+ T cells inhibit IgE responses and interleukin-4 production by CD4+ T cells

There is a growing body of evidence which suggests that CD8⁺ T cells play an important part in regulating the IgE response to non-replicating antigens. In this study we have systematically investigated their role in the regulation of IgE and of CD4⁺ T cell responses to ovalbumin (OVA) by CD8⁺ T cell depletion in vivo. Following intraperitoneal immunization with alum-precipitated OVA, OVA-specific T cell responses were detected in the spleen and depletion of CD8⁺ T cells in vitro significantly enhanced the proliferative response to OVA. Depletion of CD8⁺ T cells in vivo 7 days after immunization failed to enhance IgE production, while depletion of CD8⁺ T cells on days 12–18 greatly enhanced the IgE response, which rose to 26 μ/ml following a second injection of anti-CD8 on day 35 and remained in excess of 1 μ/ml over 300 days afterwards. Reconstitution on day 21 of rats CD8-depleted on day 12 with purified CD8⁺ T cells from animals immunized on day 12 completely inhib ited the IgE response. This effect was antigen specific; CD8⁺ T cells from OVA-primed animals had little effect on the IgE response of bovine serum albumin immunized rats. In vivo, CD8⁺ T cell depletion decreased interferon (IFN)-γ production but enhanced interleukin (IL)-4 production by OVA-stimulated splenic CD4⁺ T cells. Furthermore, CD8⁺ T cell depletion and addition of anti-IFN-γ antibody enhanced IgE production in vitro in an IL-4-supplemented mixed lymphocyte reaction. These data clearly show that antigen-specific CD8⁺ T cells inhibit IgE in the immune response to non-replicating antigens. The data indicate two possible mechanisms: first, CD8⁺ T cells have direct inhibitory effects on switching to IgE in B cells and second, they inhibit OVA-specific IL-4 production but enhance IFN-γ production by CD4⁺ T cells.     

Peripheral CD4+ CD8- γδ T cell lymphoma: A case report with multiparameter analyses

A 72-year-old Japanese man presented with CD4+ T cell receptor (TCR) γδ T cell lymphoma involving bilateral cervical lymph nodes. No involvement by tumor was observed in the liver, spleen, nasal cavity, or bone marrow throughout his clinical course. Although the tumor adequately responded to chemotherapy and irradiation, he relapsed with short remission and a slowly aggressive clinical course, and died 24 months after onset. Simultaneous expression of TCRγδ with other T-cell antigens on the lymphoma cells was analyzed by 3-color flow cytometry (3-FCM), and showed a unique phenotype CD3+ CD4+ CD8− CD7− CD5+ CD2++ TCRαβ (WT31)- βF1-TCRγδ1 (11F2)+ TCRδ1+. Cytogenetic analysis showed 79–81 and structural abnormalities consisting of del(1) (p11) and i(17)(q10). But no abnormality was identified in chromosome 7. DNA analysis revealed gene rearrangements of TCRγ and δ, while a nongerm line band in TCRβ was aberrantly seen. These observations suggest a new subtype of γδ T-cell lymphoma, which is characterized by CD4 positivity and by a clinical course not as aggressive as other predominant subtypes.     

CD86对CD8+T细胞分化的影响

目的：探讨CD86(B7-2)对CD8^ T细胞分化的影响。方法：用限制性内切酶Xho Ⅰ酶切质粒pCDM8得到CD86基因，并将其插入pCDNA3，用BamH Ⅰ酶切鉴定。用脂质体法介导pCDNA3-CD86真核表达载体转染人肝癌细胞株HMCT／21，600μg/ml G418筛选，稳定且高表达CD86的抗性克隆用流式细胞仪进行鉴定。从健康志愿者血中分离外周血单个核细胞(PB-MC)，使PBMC与靶细胞之比为20：1，共同培养48h后，用流式细胞仪检测CD3^ T细胞内IL-4和IFN-γ的表达率。结果：成功构建pCDNA3-CD86真核表达载体；CD86在HMC7721-CD86细胞中的表达率为30．8％，而在HMC7721细胞中的表达率为0．98％；健康志愿者CD3^ T细胞内IL-4和IFN-γ的表达率分别为1．92％和24．4％；PBMC与靶细胞共同培养48h后，无论是否用IFN-α刺激，IL-4，IFN-γ的阳性比值在HMC7721-CD86转染组均大于1，而在HMC7721未转染组均小于1。结论：在细胞培养中，CD86可诱导CD8^ T细胞活化，并向Tc2表型转化。     

Involvement of p21ras activation in T cell CD69 expression

The involvement of p21^ras in the induction of the early activation antigen CD69 was investigated in T cells. Expression of a v-Ha-ras coding for a constitutively active ras protein in Jurkat cells resulted in CD69 induction on the cell surface. Transfected ras was shown to be constitutively activated and functionally efficient, since it could be immunoprecipitated in the guanosine triphosphate (GTP)-bound form and it induced transactivation of an AP-1 consensus-chloramphenicol acetyltransferase reporter gene. The requirement for ras activation in T cell receptor (TcR) CD3-mediated CD69 induction was also investigated. The expression of a dominant negative c-Ha-ras-N17 mutant markedly reduced the amount of GTP that could be immunoprecipitated from ras proteins after TcR/CD3 triggering in Jurkat cells, and concomitantly decreased TcR/CD3-mediated CD69 induction. These results suggest a central role for ras in TcR/CD3-mediated CD69 expression in T cells.     

CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease

Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.     

小细胞和非小细胞肺癌晚期患者CD3~+ CD4~+及CD3~+ CD8~+T淋巴细胞亚群的差异

目的:探索小细胞和非小细胞肺癌晚期患者CD3+CD4+及CD3+CD8+T淋巴细胞亚群是否存在差异,并为治疗提供参考。方法:选取肺癌晚期患者共65例,其中包括小细胞肺癌14例,非小细胞肺癌51例以及20例健康对照。用流式细胞仪检测研究对象外周血淋巴细胞表面CD3+CD4+及CD3+CD8+的表达情况。结果:CD3+CD4+T细胞所占比例无论是小细胞还是非小细胞肺癌晚期的患者都较健康对照显著降低;CD3+CD8+T细胞所占比例在肺癌晚期的患者较健康对照并无显著变化;CD4+/CD8+比值在小细胞肺癌晚期患者较健康对照显著下降。结论:无论是小细胞还是非小细胞肺癌晚期的患者CD3+CD4+T细胞的水平较健康人都显著降低,说明肺癌晚期患者细胞免疫功能严重受损。     

Interleukin-21 and cellular activation concurrently induce potent cytotoxic function and promote antiviral activity in human CD8 T cells

Infection with human immunodeficiency virus (HIV)-1 induces a progressive deterioration of the immune system that ultimately leads to acquired immune deficiency syndrome (AIDS). Murine models indicate that the common γ-chain (γ(c))-sharing cytokine interleukin (IL)-21 and its receptor (IL-21R) play a crucial role in maintaining polyfunctional T cell responses during chronic viral infections. Therefore, we analyzed the ability of this cytokine to modulate the properties of human CD8 T cells in comparison with other γ(c)-sharing cytokines (IL-2, IL-7, and IL-15). CD8 T cells from healthy volunteers were stimulated in vitro via T cell receptor signals to mimic the heightened status of immune activation of HIV-infected patients. The administration of IL-21 upregulated cytotoxic effector function and the expression of the costimulatory molecule CD28. Notably, this outcome was not accompanied by increased cellular proliferation or activation. Moreover, IL-21 promoted antiviral activity while not inducing HIV-1 replication in vitro. Thus, IL-21 may be a favorable molecule for immunotherapy and a suitable vaccine adjuvant in HIV-infected individuals.     

Human CD8+ cytotoxic T cell responses to adenovirus capsid proteins

Adenoviruses (Ads) cause fatal disease in allogeneic stem cell transplant recipients, but there is no established therapy. Ad-specific CD8+ T cells were detected in PBMC from healthy adults at a mean frequency of 77 per 10(5) CD8+ T cells (range 8-260) by interferon-gamma ELISPOT and cytokine flow cytometry assays. CD8+ T cell lines from 7 of 7 donors exhibited MHC-class-I-restricted killing of targets expressing the capsid protein hexon. In contrast, cytotoxicity against the capsid proteins fiber and penton base was weaker or not detected. Two HLA-A2-restricted hexon epitopes and one HLA-B-restricted epitope were identified, all of which are adjacent to or overlap an HLA-DP4-restricted epitope in the highly conserved C-terminus. Thus, hexon is the immunodominant T cell target among capsid proteins and contains multiple C-terminal epitopes conserved among serotypes. These data support evaluation of donor lymphocyte infusions for treatment of Ad disease post-transplant.     

CD8+ suppressor-mediated regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65

Although potentially autoreactive T cells are present even in healthy subjects, most individuals do not develop autoimmune disease. It has been well demonstrated that CD4+ CD25+ regulatory T cells play a significant role in controlling the expansion of autoreactive T cells in the periphery. However, some healthy individuals exhibit measurable responses to self peptide even in the presence of CD4+ CD25+ regulatory cells. This article describes the regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65 (GAD65), an autoantigen implicated in type-1 diabetes, by autologous CD8+ suppressor T cells. In cells cultured from healthy individuals, the inclusion of autologous CD8+ T cells at physiological levels resulted in a dramatic decrease in the magnitude of in vitro CD4+ T cell responses to GAD65 peptide. Based on transwell experiments, the observed suppression was cell contact-dependent. However, antibody blocking studies indicated that suppression was mediated by IL-10. Cell fractionation studies suggested that CD8+ suppressor T cells originate from the CD45RA+ CD27- population. The suppression of CD4+ T cell responses to GAD65 in healthy individuals raises the possibility that CD8+ suppressor T cells play an important role in controlling potentially autoreactive T cells in the general population.     

Th17细胞联合CD3+CD8-IL-21+T细胞升高与宫颈癌发生发展的关系

目的: Th17细胞在免疫调节中起重要作用,而IL-21与Th17在分化调节和功能行使上密切相关。本研究旨在探讨Th17在宫颈癌发生发展中的作用。方法: 选取37例宫颈癌患者、25例宫颈上皮内瘤变(CIN)患者和18例健康志愿者作为研究对象,用流式细胞分析术检测外周血中Th17细胞及CD3⁺CD8^-IL-21⁺T细胞的比例。分析两者与临床病理指标之间的关系。结果: 与健康对照组相比,Th17细胞及CD3⁺CD8^-IL-21⁺ T细胞比例(占淋巴细胞百分比)在CIN组(P<0.01,P<0.05)及宫颈癌组(P<0.01,P<0.05)均明显升高。此外,2种细胞的比例都与临床分期有关,在晚期宫颈癌组明显升高(均P<0.05),并且有淋巴结转移组或脉管浸润组都明显高于相对应的无转移组(P<0.01, P<0.05)或无浸润组(均P<0.01)。此外,在健康对照组和宫颈癌组,Th17与CD3⁺CD8^-IL-21⁺ T细胞呈正相关,CD3⁺CD8^-IL-21⁺ T细胞的比例还与肿瘤大小有关(P<0.01)。结论: Th17和CD3⁺CD8^-IL-21⁺ T细胞在宫颈癌患者外周血中的比例上调,在宫颈癌的发生发展中可能起着重要作用。     

Circulating memory CD8+ T cells are limited in forming CD103+ tissue-resident memory T cells at mucosal sites after reinfection

Tissue-resident memory CD8⁺ T cells (T_RM) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (T_CM) and effector memory CD8⁺ T cells (T_EM) also contribute to tissue recall responses, but their potential to form mucosal T_RM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of T_CM and T_EM at mucosal sites. Donor T_CM and T_EM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-β stimulation. Upon pathogen clearance, T_CM and T_EM readily gave rise to secondary T_EM. T_CM also formed secondary central memory in lymphoid tissues and T_RM in internal tissues, for example, the liver. Both T_CM and T_EM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal T_RM, but not liver T_RM, efficiently reformed CD103⁺ T_RM. Our findings demonstrate that circulating T_CM and T_EM are limited in generating mucosal T_RM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8⁺ T cells for protection at mucosal sites.