Mutations in the transcription factor FOXO1 mimic positive selection signals to promote germinal center B cell expansion and lymphomagenesis

1. Download : Download high-res image (163KB)
2. Download : Download full-size image

     

RvD1 treatment during primary infection modulates memory response increasing viral load during respiratory viral reinfection

Resolvin D1 (RvD1), which is biosynthesized from essential long-chain fatty acids, is involved in anti-inflammatory activity and modulation of T cell response. Memory CD8+ T cells are important for controlling tumor growth and viral infections. Exacerbated inflammation has been described as impairing memory CD8+ T cell differentiation. This study aimed to verify the effects of RvD1 on memory CD8+ T cells in vitro and in vivo in a respiratory virus infection model. Peripheral blood mononuclear cells were treated at different time points with RvD1 and stimulated with anti-CD3/anti-CD28 antibodies. Pre-treatment with RvD1 increases the expansion of memory CD8+ T cells. The IL-12 level, a cytokine described to control memory CD8+ T cells, was reduced with RvD1 pre-treatment. When the mTOR axis was inhibited, the IL-12 levels were restored. In a respiratory virus infection model, Balb/c mice were treated with RvD1 before infection or after 7 days after infection. RvD1 treatment after infection increased the frequency of memory CD8+ T cells in the lung expressing II4, II10, and Ifng. During reinfection, RvD1-treated and RSV-infected mice present a high viral load in the lung and lower antibody response in the serum. Our results show that RvD1 modulates the expansion and phenotype of memory CD8+ T cells but contributed to a non-protective response after RSV reinfection.     

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

Simian immunodeficiency viruses (SIVs) comprise a large group of lentiviruses that infect over 45 African primate species, including numerous guenons (Cercopithecus spp.), African green monkeys (Chlorocebus spp.), mandrills and drills (Mandrillus spp.), mangabeys (Cercocebus spp.), colobus monkeys (Colobus spp., Piliocolobus spp.), as well as chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla) (1). Although the prevalence rates and geographic distribution of these infections vary widely, most SIVs are host-specific (i.e., their genomes form species-specific clusters in phylogenetic trees) (2–5). This has enabled the identification of instances when SIVs have crossed species barriers, including from apes and monkeys to humans (6). Phylogenetic analyses have shown that both pandemic and nonpandemic forms of HIV type 1 (HIV-1) resulted from the cross-species transmission of SIVs infecting central chimpanzees (P. troglodytes troglodytes) and western lowland gorillas (G. gorilla gorilla), while the various groups of HIV type 2 (HIV-2) emerged following the transfer of SIVsmm strains naturally infecting sooty mangabeys (Cercocebus atys) (6–9).SIVs have also jumped between nonhuman primate species, generating new SIV lineages. Cross-species transmission and recombination between ancestors of viruses today infecting greater spot-nosed (Cercopithecus nictitans), mustached (Cercopithecus cephus) and mona (Cercopithecus mona) monkeys (SIVgsn/SIVmus/SIVmon), and SIVrcm infecting red-capped mangabeys (Cercocebus torquatus) gave rise to SIVcpz in chimpanzees (10), and onward transmission of this virus to western lowland gorillas generated SIVgor (11). Additional cross-species transmissions and recombination events have generated mosaic SIV lineages in green monkeys (Chlorocebus sabaeus) and mandrills (Mandrillus sphinx) (12, 13). Finally, repeated introductions of diverse SIVs into the same primate species have resulted in cocirculating lineages, such as SIVkcol1 and SIVkcol2 in Kibale black-and-white colobus (Colobus guereza), and SIVmus-1, SIVmus-2, and SIVmus-3 in mustached monkeys (14, 15). Thus, primate lentiviruses have a high propensity to cross species barriers and have done so on numerous occasions throughout their evolutionary history.Lentiviruses have existed for tens of millions of years as evidenced by the finding of endogenous viruses in the genomes of species from four orders of mammals, including lemurs (16, 17), colugos (18), rabbits (19, 20), and weasels (21, 22). Some SIVs, such as those infecting green monkeys (Chlorocebus spp.) (23, 24) and the lhoesti group of guenons (Allochrocebus spp.) (25, 26) are at least several million years old because they appear to have coevolved with their respective hosts since these diverged from a common ancestor. Although an upper limit of 6 to 10 million y has been suggested for SIVs based on the fact that they have so far been found only in African, but not Asian, lineages of Old World monkeys (6), certain features of antiviral defense genes suggest that monkeys may have been exposed to lentiviruses long before this (27). Cellular restriction factors, such as APOBEC3G and TRIM5, are exquisitely antiviral and are counteracted by dedicated SIV accessary proteins. These restriction factors have evolved under strong positive selection at sites specifically involved in the interaction with lentiviruses, in both African and Asian monkeys (28, 29). However, if SIV indeed infected the common ancestor of African and Asian monkeys, this would imply numerous subsequent infection losses from multiple host lineages. Thus, it remains unclear when lentiviruses first infected primates.Among lentiviruses, those infecting primates are unique in their use of the CD4 receptor for entry into target cells. The viral envelope glycoprotein (Env) interacts with CD4 and subsequently undergoes conformational changes to expose the coreceptor binding site, which is required for viral–cell membrane fusion (30). CD4 is an immunoglobulin-like integral membrane protein that is expressed on multiple immune cells and stabilizes the interaction of the T cell receptor (TCR) with major histocompatibility complex class II (MHC II) molecules (31, 32). The most outward domain of CD4 (the D1 domain) binds a nonpolymorphic region on MHC II, which enhances TCR signaling (32). Importantly, the D1 domain is also the region that is bound by the HIV/SIV Env glycoprotein (33, 34). In HIV-infected humans and SIVmac-infected macaques, continuous high level viral replication leads to CD4⁺ T cell depletion, systemic immune activation, T cell exhaustion, and the development of AIDS (35, 36). Naturally occurring SIVs can also cause immunodeficiency and disease, as shown for chimpanzees and mandrills (37–40), indicating that these viruses are intrinsically pathogenic (41–43). However, a number of primate species with presumed longstanding SIV infections, such as African green monkeys, sooty mangabeys, and Ugandan red colobus monkeys (Piliocolobus tephrosceles), have evolved unique mechanisms that prevent disease progression despite continuous high viral replication (44–48). While the time required to evolve these adaptations is unknown, such protective mechanisms are absent from hosts that acquire new SIV infections.Unlike restriction factors, which prevent or limit viral replication, CD4 is a dependency factor (i.e., a host protein that is required for successful infection). Since there are many examples of host receptors coevolving with pathogens (49–51), it has been assumed that pressures exerted by pathogenic SIVs are responsible for the rapid diversification of primate CD4 (52–54). However, direct evidence for this hypothesis has been lacking. Examining the functional consequences of CD4 diversity in chimpanzees, we recently found that naturally occurring amino acid replacements in the D1 domain were able to inhibit SIVcpz infection, both in vitro and in vivo (55). Protective mechanisms included charged residues at the CD4–Env interface and steric hindrance between CD4- and Env-encoded glycans, which were effective not only against SIVcpz but also other SIVs that chimpanzees frequently encounter. These results suggested that CD4 diversity protects wild chimpanzee populations from SIV infection, possibly by conferring a heterozygote advantage (55). Since humans lack polymorphisms and glycans in the D1 domain, we asked whether CD4 diversification was a unique adaptation of chimpanzees. Sequencing the D1 domain in members of 36 African primate species, we identified a remarkable degree of CD4 diversity, both within and between species. The observed polymorphisms altered the cell entry of a panel of diverse SIV Envs, with the level of restriction depending on the particular allele and virus strain analyzed. Thus, the diversification of the primate CD4 receptor appears to have resulted from an ancient arms race between primate lentiviruses and their hosts.     

不同类型的急性脑梗死患者辅助性T细胞及甲基CpG结合蛋白2表达水平变化及其临床意义

目的 探讨不同类型的急性脑梗死患者辅助性T细胞(CD4⁺T cells,CD4⁺T细胞)及甲基CpG结合蛋白2(Methyl-CpG-binding protein 2,MECP2)表达水平变化及其临床意义。方法 选取本院2017年2月-2019年2月收治的急性脑梗死患者156例作为病例组,按照请奥加兰(Orgaran,ORG)治疗急性脑卒中临床研究(Trial of ORG 10172 in acute stroke treatment,TOAST)分型对病例组进行分组:A组(n=82)为大动脉粥样硬化组,B组(n=33)为心源性栓塞组,C组(n=41)为小动脉闭塞组; 同期体检健康者155例作为对照组; 检测156例病例组和155例体检健康者外周血中CD4⁺ T细胞、MeCP2表达水平。结果 A组CD4⁺ T细胞表达水平明显低于B组、C组以及对照组(P<0.05); B组CD4⁺ T细胞表达水平明显高于C组和对照组(P<0.05)。病例组MeCP2表达水平明显高于对照组(P<0.05); A组MeCP2表达水平明显高于B组、C组和对照组(P<0.05)。CD4⁺细胞表达水平与A组呈负相关(B=-1.822,P<0.001)。结论 不同急性脑梗死亚型中CD4⁺T细胞表达水平不一样,对于大动脉粥样硬化型的脑梗死患者CD4⁺T细胞表达水平下降,而MeCP2表达水平的升高也预示急性脑梗死的风险增大,说明CD4⁺T细胞表达水平检测对于急性脑梗死的分型具有一定的意义,而MeCP2表达水平的变化可以作为预防急性脑梗死的重要指标。     

Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging

1. Download : Download high-res image (177KB)
2. Download : Download full-size image

     

Identification of CD56dim subpopulation marked with high expression of GZMB/PRF1/PI-9 in CD56+ interferon-α-induced dendritic cells

As the sentinels of innate and adaptive immune system, dendritic cells (DCs) have been considered to hold a great promise for medical application. Among the diverse types of DCs, monocyte-derived DCs (mo-DCs) generated in vitro have been most commonly employed. We have been improving the culture protocol and devised a protocol to produce mature interferon-α-induced DCs (IFN-DCs), hereinafter called (mat)IFN-DCs. While exploring the relationship between the expression of CD56 and the cytotoxic activity of (mat)IFN-DCs, we unexpectedly found that sorting of (mat)IFN-DCs with CD56 antibody-coated microbeads (MB) resulted in fractionating cells with tumoricidal activity into the flow-through (FT) but not MB-bound fraction. We uncovered that the FT fraction contains cells expressing low but substantial level of CD56. Moreover, those cells express granzyme B (GrB), perforin (PFN), and serpin B9 at high levels. By employing a specific inhibitor of PFN, we confirmed that direct tumoricidal activity relies on the GrB/PFN pathway. We designated subpopulation in FT fraction as CD56^dim and that in CD56 positively sorted fraction as CD56^bright, respectively. This is the first time, to our knowledge, to identify subpopulations of CD56-positive IFN-DCs with distinct tumoricidal activity which is ascribed to high expression of the components of GrB/PFN pathway.     

中药影响实验性自身免疫性脑脊髓炎CD4+T细胞亚群分化的研究进展

实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)是由CD4⁺T细胞介导的中枢神经系统脱髓鞘性疾病,是国际公认研究多发性硬化(multiple sclerosis,MS)的动物模型。CD4⁺T细胞作为EAE模型的主要免疫应答细胞,存在多个亚群,可分泌多种细胞因子,参与病情进展。CD4⁺T细胞增殖分化及功能紊乱与EAE发病机制密切相关。目前临床尚无治疗MS的有效药物,多以对症应用皮质类固醇激素为主,但不良反应严重,且易产生药物依赖。近年来中药因作用温和、药物安全性较高、成本低、耐受性好等优点逐渐走进大众视野,针对中药对EAE中CD4⁺T细胞亚群分化的影响展开论述,为临床用药提供更多理论基础。