Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes

CD8+CD25+ cells, which expressed high levels of Foxp3, glucocorticoid-induced tumor necrosis factor receptor (GITR), CCR8, tumor necrosis factor receptor 2 (TNFR2), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) mRNAs, were identified in the fibrous septa and medullary areas of human thymus. Activated CD8+CD25+ thymocytes did not produce cytokines, but most of them expressed surface CTLA-4 and transforming growth factor beta1 (TGF-beta1). Like CD4+CD25+, CD8+CD25+ thymocytes suppressed the proliferation of autologous CD25-T cells via a contact-dependent mechanism. The suppressive activity of CD8+CD25+ thymocytes was abrogated by a mixture of anti-CTLA-4 and anti-TGF-beta1 antibodies and it was mediated by their ability to inhibit the expression of the interleukin 2 receptor alpha chain on target T cells. These results demonstrate the existence of a subset of human CD8+CD25+ thymocytes sharing phenotype, functional features, and mechanism of action with CD4+CD25+ T regulatory cells.     

非小细胞肺癌患者CD3+、CD4+、CD8+、CD44+表达的临床研究

目的研究非小细胞肺癌患者外周血淋巴细胞中CD3+、CD4+、CD8+、CD4+4的表达水平。方法取65例非小细胞肺癌患者及22例健康正常人外周静脉血,应用流式细胞仪检验非小细胞肺癌患者(实验组)与健康人外周血淋巴细胞中(对照组)CD3+、CD4+、CD8+、CD4+4的表达水平。结果实验组与对照组CD3+、CD3+CD4+、CD3+CD8+、CD4+4在淋巴细胞中的比例存在显著性差异(P<0.05),其中,实验组占总淋巴细胞的比例分别为48.07±10.33%、30.93±6.68%、17.13±3.37%、55.45±4.35%;对照组CD3+、CD3+CD4+、CD3+CD8+、CD4+4占总淋巴细胞的比例分别为58.83±10.88%、34.89±6.45%、23.91±4.42%、62.85±7.56%;但鳞癌与腺癌组CD4+4的表达无显著性差异(P>0.05),其中,鳞癌组CD4+4所占比例为61.32±8.06%,腺癌组为64.43±6.76%。结论非小细胞肺癌患者外周血T细胞亚群及CD4+4的表达水平较正常组均低,其表达水平与组织类型无关。     

Decrease in CD4+CD25+ and CD8+CD28+ T cells in interstitial pneumonitis associated with rheumatic disease

The expression of CD25 or CD28 on T cells was examined in patients with rheumatic diseases associated with interstitial pneumonitis (IP), in order to investigate the conditions of CD4⁺CD25⁺ regulatory T cells and CD8⁺CD28⁻ suppressor T cells. Fifty-five patients with various rheumatic diseases and 23 normal controls were enrolled. CD4⁺CD25⁺ T cells of patients with IP were significantly decreased in comparison with non-IP patients, and the ratio of CD8⁺CD28⁻ T cells in patients with IP was significantly higher than that in non-IP patients or normal controls. These results for CD8⁺CD28⁻ T cells were in accord with the decrease in CD8⁺CD28⁺ T cells, and may be related to activation-induced CD8⁺CD28⁺ T-cell death. Thus, the abnormality of CD4⁺CD25⁺ regulatory T cells may be related to the pathogenesis of IP, and the survival and activation of CD8⁺ T cells.     

Decrease in CD4+CD25+ and CD8+CD28+ T cells in interstitial pneumonitis associated with rheumatic disease

Abstract

The expression of CD25 or CD28 on T cells was examined in patients with rheumatic diseases associated with interstitial pneumonitis (IP), in order to investigate the conditions of CD4⁺CD25⁺ regulatory T cells and CD8⁺CD28^? suppressor T cells. Fifty-five patients with various rheumatic diseases and 23 normal controls were enrolled. CD4⁺CD25⁺ T cells of patients with IP were significantly decreased in comparison with non-IP patients, and the ratio of CD8⁺CD28^? T cells in patients with IP was significantly higher than that in non-IP patients or normal controls. These results for CD8⁺CD28^? T cells were in accord with the decrease in CD8⁺CD28⁺ T cells, and may be related to activation-induced CD8⁺CD28⁺ T-cell death. Thus, the abnormality of CD4⁺CD25⁺ regulatory T cells may be related to the pathogenesis of IP, and the survival and activation of CD8⁺ T cells.     

CD19+CD5+ cells as indicators of preeclampsia

Preeclampsia is a devastating pregnancy-associated disorder affecting 5% to 8% of pregnant women worldwide. It emerges as an autoimmune-driven disease, and, among others, the autoantibodies against angiotensin type 1 receptor II have been proposed to account for preeclampsia symptoms. Despite much attention focused on describing autoantibodies associated with preeclampsia, there is no clue concerning the cell population producing them. CD19(+)CD5(+) B-1a B cells constitute the main source of natural and polyreactive antibodies, which can be directed against own structures. Here, we aimed to identify the B-cell subpopulation responsible for autoantibody production during preeclampsia and to study their regulation, as well as their possible use as markers for the disease. The frequency of CD19(+)CD5(+) cells in peripheral blood of preeclamptic patients is dramatically increased compared with normal pregnant women as analyzed by flow cytometry. This seems to be driven by the high human chorionic gonadotropin levels present in the serum and placenta supernatant of preeclamptic patients versus normal pregnant women. Not only ≈95% of CD19(+)CD5(+) cells express the human chorionic gonadotropin receptor, but these cells also expand on human chorionic gonadotropin stimulation in a lymphocyte culture. Most importantly, isolated CD19(+)CD5(+) cells produce autoantibodies against angiotensin type 1 receptor II, and CD19(+)CD5(+) cells were further detected in the placenta of preeclamptic but not of normal pregnancies where barely B cells are present. Our results identify a B-cell population able to produce pregnancy-pathological autoantibodies as possible markers for preeclampsia, which opens vast diagnostic and therapeutic applications.     

CD4+CD25+调节性T细胞与支气管哮喘

支气管哮喘是一种常见的慢性呼吸道疾病,其免疫发病机制尚不十分清楚。CD4 CD25 调节性T细胞是一种特殊的调节性T细胞,参与自身免疫调节,维持自身免疫耐受。本文就CD4 CD25 调节性T细胞的特性及与支气管哮喘的发病机制、治疗、预后的研究进展做一综述。     

CD4+ and CD56+ acute monoblastic leukemia.

We report here a patient with acute monoblastic leukemia whose leukemia cells had CD4 (T4) and CD56 (NKH-1) antigens, in addition to CD36 (OKM5) antigen. The leukemia cells did not have NK or ADCC activities. They showed no rearrangements of immunoglobulin heavy (IgH) chain and T cell receptor (TCR)-beta chain genes, indicating that the leukemia cells were nonlymphoid. The presence of this case suggests that leukemia cells could be originated from monocytes with NK-associated antigen without IgH or TCR rearrangements.     

CD4+ CD56+ Hematodermic Neoplasm Without Cutaneous Involvement

First evidence of cases of haemophilia dates from ancient Egypt, but it was when Queen Victoria from England in the 19th century transmitted this illness to her descendants, when it became known as the “royal disease”. Last decades of the 20th century account for major discoveries that improved the life expectancy and quality of life of these patients. The history and evolution of haemophilia healthcare counts ups and downs. The introduction of prophylactic schemes during the 1970s have proved to be more effective that the classic on-demand replacement of clotting factors, nevertheless many patients managed with frequent plasma transfusions or derived products became infected with the Human Immunodeficiency Virus (HIV) and Hepatitis C virus during the 1980s and 1990s. Recombinant factor VIII inception has decreased the risk of blood borne infections and restored back longer life expectancies. Main concerns for haemophilia healthcare are shifting from the pure clinical aspects to the economic considerations of long-term replacement therapy. Nowadays researchers’ attention has been placed on the future costs and cost-effectiveness of costly long-term treatment. Equity considerations are relevant as well, and alternative options for less affluent countries are under the scope of further research. The aim of this review was to assess the evidence of different treatment options for haemophilia type A over the past four decades, focusing on the most important technological advances that have influenced the natural course of this “royal disease”.     

CD4＋CD25＋Treg细胞与支气管哮喘

CD4＋CD25＋Treg细胞的主要作用表现为免疫无能性和免疫抑制性,是外周免疫耐受形成机制的主要组成部分。其主要作用机制为分泌抑制性细胞因子（IL-10和TGF-β）、表达细胞表面分子（CTLA-4、GITR等）及Foxp3等。支气管哮喘患者外周血CD4＋CD25＋Treg功能及数量存在异常,这可能是支气管哮喘发病机制之一。糖皮质激素可以通过影响CD4＋CD25＋Treg的状态起到抑制支气管哮喘气道炎症的作用。     

CD4+CD25+T细胞与支气管哮喘

本文就CD4^＋CD25^＋T细胞的调节机制，CD4^＋CD25^＋T细胞与变态反应的关系，以及CD4^＋CD25^＋T细胞在支气管哮喘发病机制中的作用作一综述。     

CD4+CD25+Treg细胞与支气管哮喘

CD4+ CD25+ Treg细胞的主要作用表现为免疫无能性和免疫抑制性,是外周免疫耐受形成机制的主要组成部分.其主要作用机制为分泌抑制性细胞因子(IL-10和TGF-β)、表达细胞表面分子(CTLA-4、GITR等)及Foxp3等.支气管哮喘患者外周血CD4+ CD25+ Treg功能及数量存在异常,这可能是支气管哮...     

CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity

Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c⁺ cells should curtail their migration to the central nervous system (CNS) and ameliorate experimental autoimmune encephalomyelitis (EAE). We generated CD11c.Cre^+/−ITGA4^fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c⁺ cells. Active immunization and adoptive transfer EAE models were employed and compared with WT controls. Multiparameter flow cytometry was utilized to immunophenotype leukocyte subsets. Single-cell RNA sequencing was used to profile individual cells. α4-Integrin expression by CD11c⁺ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre^+/−ITGA4^fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre^+/−ITGA4^fl/fl mice, during which CD11c⁺CD88⁺ cells were sequestered in the blood. Upon clinical EAE onset, CD11c⁺CD88⁺ cells appeared in the CNS and expressed CD317⁺. In adoptive transfer experiments, CD11c.Cre^+/−ITGA4^fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c⁺CD88⁺CD317⁺ cells. In human cerebrospinal fluid from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice.

Autoimmune disorders of the central nervous system (CNS), including multiple sclerosis (MS), are thought to be mediated by aberrant adaptive immune responses against self-antigens. In experimental autoimmune encephalomyelitis (EAE), a model of MS, activated myelin-reactive CD4⁺ T helper cells are the main drivers of disease activity (1). In active EAE, dendritic cells (DC) are professional antigen-presenting cells (APC) at the inoculation site, namely in draining lymph nodes and other secondary lymphoid organs, where they present myelin autoantigen to naïve CD4⁺ T lymphocytes (2). Myeloid APC within the CNS are essential for the reactivation and retention of these autoreactive CD4⁺ T cells, and for perpetuation of disease activity. Specifically, myeloid cells within cerebral perivascular spaces previously considered DC based solely on their expression of CD11c are sufficient to permit EAE (3). Myeloid APC, including DC, use α4-integrin to gain access to sites of ongoing inflammation. We previously showed that the number of DC was significantly reduced in cerebral perivascular spaces in autopsy material of an MS patient treated with natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin (4). Conceivably, antagonizing or diminishing the function of α4-integrin selectively in myeloid cells should ameliorate EAE through an impaired reactivation of CNS-specific CD4⁺ T cells and a reduction of direct inflammatory effects exerted by these cells.To further understand the role of CD11c⁺ cells within the CNS during CD4⁺ T cell-mediated CNS autoimmunity, we generated and characterized CD11c.Cre^+/−ITGA4^fl/fl mice, which lack α4-integrin expression in CD11c⁺ cells. We identified CD11c⁺CD88⁺CD317⁺ as mediators of persistent clinical EAE, and propagators of inflammation within the CNS.     

Precommitment of CD4+CD8+ thymocytes to either CD4 or CD8 lineages.

CD4+ and CD8+ mature T cells arise from CD4+CD8+ precursors in the thymus. During this process, cells expressing T-cell receptors (TCRs) reactive with self major histocompatibility complex (MHC) class I or II molecules are positively selected to the CD8 or CD4 lineage, respectively. It is controversial whether lineage commitment of CD4+CD8+ thymocytes is controlled directly by TCR specificity for MHC (instructional model) or, alternatively, by processes that operate independently of TCR specificity (stochastic model). We show here that CD4+CD8+ thymocytes bearing a MHC class I-restricted transgenic TCR can be subject to two alternative developmental fates. One population of CD4+CD8+ cells is positively selected by MHC class I molecules to the CD8 lineage as expected, whereas the other CD4+CD8+ population rearranges endogenous TCR genes and is positively selected by MHC class II molecules to the CD4 lineage. Blocking TCR-MHC class II interactions in vivo does not interfere with the generation of CD4+CD8+ cells expressing endogenous TCRs but does prevent their subsequent maturation to CD4+ cells. These data support a version of the stochastic model in which CD4+CD8+ thymocytes are precommitted to the CD4 or CD8 lineage independently of TCR specificity for MHC and prior to positive selection.     

CD25+CD4+ T cells contribute to the control of memory CD8+ T cells

Previously we demonstrated that IL-15 and IL-2 control the number of memory CD8+ T cells in mice. IL-15 induces, and IL-2 suppresses the division of these cells. Here we show that CD25+CD4+ regulatory T cells play an important role in the IL-2-mediated control of memory phenotype CD8+ T cell number. In animals, the numbers of CD25+CD4+ T cells were inversely correlated with the numbers of memory phenotype CD8+ T cells with age. Treatment with anti-IL-2 caused CD25+CD4+ T cells to disappear and, concurrently, increased the numbers of memory phenotype CD8+ T cells. This increase in the numbers of CD8+ memory phenotype T cells was not manifest in animals lacking CD4+ cells. Importantly, adoptive transfer of CD25+CD4+ T cells significantly reduced division of memory phenotype CD8+ T cells. Thus, we conclude that CD25+CD4+ T cells are involved in the IL-2-mediated inhibition of memory CD8+ T cell division and that IL-2 controls memory phenotype CD8+ T cell numbers at least in part through maintenance of the CD25+CD4+ T cell population.     

De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells

Antigen-specificity is a hallmark of adaptive T cell-mediated immune responses. CD4+CD25+FOXP3+ regulatory T cells (T(R)) also require activation through the T cell receptor for function. Although these cells require antigen-specific activation, they are generally able to suppress bystander T cell responses once activated. This raises the possibility that antigen-specific T(R) may be useful therapeutically by localizing generalized suppressive activity to tissues expressing select target antigens. Here, we demonstrate that T(R) specific for particular peptide-MHC complexes can be generated from human CD4+CD25- T cells in vitro and isolated by using HLA class II tetramers. Influenza hemagglutinin epitopes were used to generate hemagglutinin-specific T(R), which required cognate antigen for activation but which subsequently suppressed noncognate bystander T cell responses as well. These findings have implications for the generation of therapeutic regulatory T cells in disease, and also suggest an important mechanism by which T cells may be regulated at the site of inflammation.     

Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells

Rapamycin is an immunosuppressive compound that is currently used to prevent acute graft rejection in humans. In addition, rapamycin has been shown to allow operational tolerance in murine models. However, a direct effect of rapamycin on T regulatory (Tr) cells, which play a key role in induction and maintenance of peripheral tolerance, has not been demonstrated so far. Here, we provide new evidence that rapamycin selectively expands the murine naturally occurring CD4(+)CD25(+)FoxP3(+) Tr cells in vitro. These expanded Tr cells suppress proliferation of syngeneic T cells in vitro and prevent allograft rejection in vivo. Interestingly, rapamycin does not block activation-induced cell death and proliferation of CD4(+) T cells in vitro. Based on this new mode of action, rapamycin can be used to expand CD4(+)CD25(+)FoxP3(+) Tr cells for ex vivo cellular therapy in T-cell-mediated diseases.