Decreased numbers of signal-joint T cell receptor excision circle-containing CD4+ and CD8+ cells in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) patients have a decreased number of peripheral blood T cells containing signal-joint T cell receptor excision circles (Sj TRECs), which are considered an indicator of thymic output. The objective of this study was to investigate the mechanism of the decrease in such T cells. Peripheral blood T cells from SLE patients were classified into CD4+ and CD8+ cells. Sj TREC levels were measured by real-time PCR. Telomerase activity was determined by the telomeric repeat amplification protocol assay. The numbers of Sj TREC containing CD4+ and CD8+ cells were lower in the peripheral blood of SLE patients than in the controls. A correlation was found between the numbers of Sj TREC-positive CD4+ and CD8+ cells. The level of TRECs is influenced by an increase in cell division. To examine this increase, telomerase activity as an indicator of cell division was measured simultaneously; however, there was no correlation between the Sj TREC level and telomerase activity. These results suggest that decreased thymic output occurs in SLE patients.     

RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes

Rearrangement of T cell receptor (TCR) genes is driven by transient expression of V(D)J recombination-activating genes (RAGs) during lymphocyte development. Immunological dogma holds that T cells irreversibly terminate RAG expression before exiting the thymus, and that all of the progeny arising from mature T cells express the parental TCRs. When single pancreatic islet-derived, NRP-A7 peptide-reactive CD8(+) T cells from nonobese diabetic (NOD) mice were repeatedly stimulated with peptide-pulsed dendritic cells, daughter T cells reexpressed RAGs, lost their ability to bind to NRP-A7K(d) tetramers, ceased to transcribe tetramer-specific TCR genes, and, instead, expressed a vast array of other TCR rearrangements. Pancreatic lymph node (PLN) CD8(+) T cells from animals expressing a transgenic NRP-A7-reactive TCR transcribed and translated RAGs in vivo and displayed endogenous TCRs on their surface. RAG reexpression also occurred in the PLN CD8(+) T cells of wild-type NOD mice and could be induced in the peripheral CD8(+) T cells of nondiabetes-prone TCR-transgenic B10.H2(g7) mice by stimulation with peptide-pulsed dendritic cells. In contrast, reexpression of RAGs could not be induced in the CD8(+) T cells of B6 mice expressing an ovalbumin-specific, K(b)-restricted TCR, or in the CD8(+) T cells of NOD mice expressing a lymphocytic choriomeningitis virus-specific, D(b)-restricted TCR. Extra-thymic reexpression of the V(D)J recombination machinery in certain CD8(+) T cell subpopulations, therefore, enables further diversification of the peripheral T cell repertoire.     

Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count

OBJECTIVE: To assess the absolute rate of AIDS and death in antiretroviral therapy (ART)-naive patients with a high CD4 cell count. Such information would be helpful in the design of a trial investigating early initiation of ART. DESIGN: Analysis of data from an ongoing HIV cohort study. METHODS: The rate of (severe) AIDS or death and death alone was evaluated in ART-naive patients according to the current CD4 cell count, focusing on CD4 cell counts > or = 350 cells/microl among patients in the UK CHIC Study. RESULTS: In a total of 30 313 person-years of follow-up, there were 1557 AIDS or death events. The rate of AIDS or death in persons with most recent CD4 cell count 350-499, 500-649 and > 650 cells/microl was 2.49, 1.54 and 0.96 per 100 person-years, respectively. The rate ratio for those with CD4 cell count 500-649 cells/microl compared with those with CD4 cell count > or = 650 cells/microl was 1.55 [95% confidence interval (CI), 1.11-2.17; P = 0.01]. In a Poisson regression model based on person years with CD4 cell count > or = 350 cells/microl , there was a strong effect of CD4 cell count on rate of AIDS or death (rate ratio, 0.84; 95% CI, 0.76-0.93; P = 0.001), independent of viral load and age. CONCLUSIONS: The trend of decreasing rate of AIDS and death with higher CD4 cell count is present throughout the CD4 cell count > or = 350 cells/microl range in ART-naive people.     

儿童和青少年自身免疫性肝炎患者外周血淋巴细胞亚群变化及其临床意义探讨

目的 研究儿童和青少年AIH患者外周血淋巴细胞亚群的变化及其临床意义。 方法 2015年6月～2019年1月我院收治的儿童和青少年AIH患者42例和健康儿童和青少年50例,使用流式细胞仪检测外周血单个核细胞表面标志物。结果 AIH患者外周血CD4⁺T细胞百分比为53.1(42.5,57.8)%,显著高于健康人,而CD14⁺T细胞百分比为62.2(40.1,76.8)%,显著低于健康人,而两组外周血CD8⁺T细胞百分比无显著性差异【25.9(12.5,32.4)%对18.7(12.8,28.5)%,P>0.05);AIH患者外周血CD4⁺T淋巴细胞表面CD45RA、CD45RO、CCR3和CD28表达百分比分别为26.1(15.2,32.8)%、19.2(13.5,27.3)%、15.4(2.1,53.8)%和51.2(34.4,56.9)%,均显著高于健康人;AIH患者外周血CD8⁺T淋巴细胞表面CD45RA、CCR3和CD25表达百分比分别为18.0(14.1,26.8)%、1.2(0.5,3.2)%和0.6(0.3,7.8)%,显著高于健康人【分别为13.6(8.2,18.3)%、0.5(0.3,0.6)%和0.3(0.2,0.5)%, P<0.05],而外周血CD8⁺T淋巴细胞表面CD45RO表达百分比为2.7(2.3,4.8)%,显著低于健康人;AIH患者外周血CD14⁺T淋巴细胞表面CD45R0表达百分比为 34.7(16.3,57.8)%,显著低于健康人。结论 外周血CD4⁺、CD8⁺和CD14⁺T 细胞比例失衡及其细胞表面分子表达异常与AIH患者发病或病情进展密切相关,值得进一步研究。     

Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis

A significant number of self-reactive T cell clones escape thymic negative selection and are released into the periphery, where some are potentially pathogenic. The clonal expansion of self-reactive T cells is known to be limited during initial antigen encounter by apoptotic or anergic mechanisms, regulatory CD4+ T cells, and cytokines. Here we report that superimposed on these mechanisms, during the evolution of autoimmunity in experimental autoimmune encephalomyelitis (EAE), CD8+ T cells are induced, which fine-tune the peripheral self-reactive T cell receptor (TCR) repertoire. We assayed the myelin basic protein-reactive TCR repertoire in naive, EAE-recovered mice as well as EAE-recovered mice depleted of CD8+ T cells by TCRV beta surface expression, complementarity-determining region 3 length distribution, and complementarity-determining region 3 sequencing analysis. In EAE-recovered mice, certain myelin basic protein-reactive CD4+V beta 8.2+ clones are significantly decreased and this decrease is not observed if CD8+ T cells were depleted from these mice. The clones that persist in CD8+ T cell-intact mice are highly diverse in contrast to the clones expanded in CD8+ T cell-depleted mice, which are dominated by the significant outgrowth of a few clones. Importantly, the T cell clones that expand in the absence of CD8+ T cell control are enriched in potentially pathogenic self-reactive T cell clones capable of inducing EAE in vivo.     

Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals

HIV infection induces a wide array of B cell dysfunctions. We have characterized the effect of plasma viremia on the responsiveness of B cells to CD4(+) T cell help in HIV-infected patients. In HIV-negative donors, B cell proliferation correlated with CD154 expression on activated CD4(+) T cells and with the availability of IL-2, whereas in HIV-infected viremic patients, reduced B cell proliferation was observed despite normal CD154 expression on activated CD4(+) T cells. Reduced triggering of B cells by activated CD4(+) T cells was clearly observed in HIV-infected viremic patients compared with aviremic patients with comparable CD4(+) T cell counts, and a dramatic improvement in B cell function was observed in patients whose plasma viremia was controlled by effective antiretroviral therapy. The degree of B cell dysfunction in viremic patients correlated strongly with the inability of B cells to express CD25 in response to activated CD4(+) T cells, resulting in an inability to mount a normal proliferative response to IL-2. Similar defects in responsiveness to IL-2 were observed in the B cells of HIV-infected viremic patients in the context of B cell receptor stimulation. These data provide new insight into the mechanisms associated with ineffective humoral responses in HIV disease.     

Monkeypox virus evades antiviral CD4+ and CD8+ T cell responses by suppressing cognate T cell activation

Monkeypox virus (MPV) is a virulent human pathogen that has gained increased attention because of its potential use as a bioterrorism agent and inadvertent introduction into North America in 2003. The US outbreak also provided an important opportunity to study MPV-specific T cell immunity. Although MPV-specific CD4⁺ and CD8⁺ T cells could recognize vaccinia virus (VV)-infected monocytes and produce inflammatory cytokines such as IFNγ and TNFα, they were largely incapable of responding to autologous MPV-infected cells. Further analysis revealed that, unlike cowpox virus (CPV), MPV did not interfere with MHC expression or intracellular transport of MHC molecules. Instead, MPV-infected cells were capable of preventing T cell receptor (TcR)-mediated T cell activation in trans. The ability to trigger a state of nonresponsiveness represents a unique MHC-independent mechanism for blocking antiviral T cell activation and inflammatory cytokine production and is likely an important attribute involved with viral dissemination in the infected host.     

Relationship between the frequency of HIV-specific CD8+ T cells and the level of CD38+CD8+ T cells in untreated HIV-infected individuals

CD8+ T cells are critical for effective host defenses against viral infections. Studies addressing HIV-induced immune responses in infected individuals have suggested that CD8+ T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8+ T cells, HIV is not contained in many untreated patients. Active HIV replication is associated with numerous immunologic changes, the most notable and consistent of which is an increase in CD8+ T cells expressing CD38. Previous studies have demonstrated that the expression of CD38 on CD8+ T cells is associated with poor prognostic outcome in infected individuals with detectable plasma viremia; however, the relationship between the expression of CD38 and the frequency of HIV-specific CD8+ T cells is unclear. We demonstrate a correlation between levels of HIV-specific CD8+ T cells and levels of CD8+ T cells expressing CD38 in untreated patients. The distribution of HIV-specific CD8+ T cells was heavily skewed toward CD38+CD8+ T cells in patients with a high percentage of CD38+CD8+ T cells. Spontaneous/Fas-mediated apoptosis in CD38+CD8+ T cells was significantly higher in patients with high percentages of CD38+CD8+ T cells. Our data suggest that a substantial proportion of the HIV-specific CD8+ T cells present in CD38+CD8+ T cells in patients with active viral replication arise by HIV-driven aberrant immune activation and may not manifest effective cytolytic activity against infected targets due to a high degree of susceptibility to apoptosis, thus providing an explanation of why HIV is not successfully contained by CD8+ T cells in such individuals.     

Toll样受体、CD4+CD25+调节性T细胞与支气管哮喘的关系

Toll样受体（TLR）是机体识别环境中各种微生物的主要受体，是介导天然免疫和获得性免疫的桥梁。支气管哮喘（哮喘）的发病是环境和基因相互作用的结果，TLR与哮喘有着十分密切的关系。近年来，人们逐渐认识到Th1／Th2理论并不能充分阐明哮喘的发病机制。随着对哮喘的深入研究，CD4^＋CD25^＋调节性T细胞凸现其冰山一角。本文就近年来对TLR、CD4^＋CD25^＋调节性T细胞和哮喘关系的研究进展作一综述。     

Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients

Several studies have reported enhanced oxidative stress in patients with HIV infection. An important pathophysiologic consequence of increased oxidative stress is endogenous DNA damage, and the base excision repair pathway is the most important mechanism to withstand such deleterious effects. To investigate the role of base excision repair in HIV infection, we examined 7,8-dihydro-8-oxoguanine (8-oxoG) levels as a marker of oxidative DNA damage and DNA glycosylase activities in CD4(+) and CD8(+) T cells of HIV-infected patients and controls. These results showed that the HIV-infected patients, particularly those with advanced disease, had increased levels of 8-oxoG in CD4(+) T cells and marked declines in DNA glycosylase activity for the repair of oxidative base lesions in these cells. In contrast, CD8(+) T cells from HIV-infected patients, with 8-oxoG levels similar to those in healthy controls, showed enhanced capacity to repair oxidative DNA damage. Finally, highly active antiretroviral therapy induced increased glycosylase activity in CD4(+) T cells and normalized 8-oxoG levels. This imbalance between the accumulation of oxidative DNA damage and the capacity to repair such lesions in CD4(+) T cells may represent a previously unrecognized mechanism involved in the numerical and functional impairment of CD4(+) T cells in patients with HIV infection.     

Potent induction of long-term CD8+ T cell memory by short-term IL-4 exposure during T cell receptor stimulation

An important goal of vaccination is to achieve long-term survival of functional memory T cells. Using a MHC-compatible adoptive transfer system, we show here that a short, 3-day IL-4 but not IL-2 or IL-12 exposure during in vitro T cell receptor stimulation of naive CD8(+) T cells induced long-lasting in vivo memory. Such long-term memory CD8(+) T cells expressed antigen-specific cytotoxicity and the potential for IFN-gamma and IL-4 production. Our results support the concept that functional T cell longevity can be regulated by cytokines during initial antigen encounter and provide a rational foundation for vaccine development. They also may have implications in formulating optimal therapeutic regimens of ex vivo expanded autologous cancer- and HIV-specific CD8(+) T cells. In addition, the availability of large numbers of memory CD8(+) T cells generated through our high-efficiency system should facilitate progress in the molecular dissection of CD8(+) T cell memory development.     

CD8 T-cell subsets and viral load in the cerebrospinal fluid of therapy-naive HIV-infected individuals

Central nervous system involvement is common in HIV infection. We determined the relationship between T-cell subsets and viral load in the cerebrospinal fluid (CSF) of therapy-naive, asymptomatic HIV-infected individuals. A shift from naive to effector-memory CD8 T cells was observed in the CSF of HIV-infected individuals compared with controls. The HIV load strongly correlated with CD8 T cells in CSF. Effector-memory CD8 T cells were positively and effector CD8 T cells were negatively associated with viral replication in CSF.     

Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients

To evaluate the effects of HIV infection on T cell turnover, we examined levels of DNA synthesis in lymph node and peripheral blood mononuclear cell subsets by using ex vivo labeling with BrdUrd. Compared with healthy controls (n = 67), HIV-infected patients (n = 57) had significant increases in the number and fraction of dividing CD4(+) and CD8(+) T cells. Higher percentages of dividing CD4(+) and CD8(+) T cells were noted in patients with the higher viral burdens. No direct correlation was noted between rates of T cell turnover and CD4(+) T cell counts. Marked reductions in CD4(+) and CD8(+) T cell proliferation were seen in 11/11 patients 1-12 weeks after initiation of highly active antiretroviral therapy (HAART). These reductions persisted for the length of the study (16-72 weeks). Decreases in naive T cell proliferation correlated with increases in the levels of T cell receptor rearrangement excision circles. Division of CD4(+) and CD8(+) T cells increased dramatically in association with rapid increases in HIV-1 viral loads in 9/9 patients 5 weeks after termination of HAART and declined to pre-HAART-termination levels 8 weeks after reinitiation of therapy. These data are consistent with the hypothesis that HIV-1 infection induces a viral burden-related, global activation of the immune system, leading to increases in lymphocyte proliferation.     

Relationship of CD8(+) T cell noncytotoxic anti-HIV response to CD4(+) T cell number in untreated asymptomatic HIV-infected individuals

During chronic HIV infection, asymptomatic individuals demonstrate a strong CD8(+) cell noncytotoxic antiviral response (CNAR). With the onset of symptoms or reduction in CD4(+) cell counts, CNAR decreases. Presently, it is recommended that infected individuals receive antiretroviral therapy if CD4(+) cell counts fall below 350 cells/microL. To determine whether CNAR lends support to this recommendation for initiation of antiretroviral treatment, we examined CNAR in 20 healthy, untreated, HIV-infected men exhibiting a range of CD4(+) cell numbers. Our results indicate that the asymptomatic untreated HIV-infected individuals with less than 300 CD4(+) cells/microL had a significantly lower CNAR than those with higher CD4(+) cell counts. These data on CNAR in untreated, healthy, HIV-infected individuals support the current recommendation for when to initiate antiretroviral therapy.