Recognition of a ubiquitous self antigen by prostate cancer-infiltrating CD8+ T lymphocytes

Substantial evidence exists that many tumors can be specifically recognized by CD8+ T lymphocytes. The definition of antigens targeted by these cells is paramount for the development of effective immunotherapeutic strategies for treating human cancers. In a screen for endogenous tumor-associated T cell responses in a primary mouse model of prostatic adenocarcinoma, we identified a naturally arising CD8+ T cell response that is reactive to a peptide derived from histone H4. Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection.     

The role of CCR7 in TH1 and TH2 cell localization and delivery of B cell help in vivo

Subsets of murine CD4+ T cells localize to different areas of the spleen after adoptive transfer. Na?ve and T helper 1 (TH1) cells, which express the chemokine receptor CCR7, are home to the periarteriolar lymphoid sheath, whereas activated TH2 cells, which lack CCR7, form rings at the periphery of the T cell zones near B cell follicles. Retroviral transduction of TH2 cells with CCR7 forces them to localize in a TH1-like pattern and inhibits their participation in B cell help in vivo but not in vitro. Thus, differential expression of chemokine receptors results in unique cellular migration patterns that are important for effective immune responses.     

The role of B cells for in vivo T cell responses to a Friend virus-induced leukemia

B cells can function as antigen-presenting cells and accessory cells for T cell responses. This study evaluated the role of B cells in the induction of protective T cell immunity to a Friend murine leukemia virus (F-MuLV)-induced leukemia (FBL). B cell-deficient mice exhibited significantly reduced tumor-specific CD4+ helper and CD8+ cytotoxic T cell responses after priming with FBL or a recombinant vaccinia virus containing F-MuLV antigens. Moreover, these mice had diminished T cell responses to the vaccinia viral antigens. Tumor-primed T cells transferred into B cell-deficient mice effectively eradicated disseminated FBL. Thus, B cells appear necessary for efficient priming but not expression of tumor and viral T cell immunity.     

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

The delivery of CD4 help to CD8+ T cell responses requires interactions between CD40 and CD40 ligand and is thought to occur through antigen-presenting cell (APC) activation. Here we show that generation of memory CD8+ T cells displaying an enhanced capacity for cell division and cytokine secretion required CD4 help but not CD40 expression by the APCs. Activated CD4+ and CD8+ T cells expressed CD40; and in the absence of this protein, CD8+ T cells were unable to differentiate into memory cells or receive CD4 help. These results suggest that, like B cells, CD8+ T cells receive CD4 help directly through CD40 and that this interaction is fundamental for CD8+ T cell memory generation.     

雏鸡免疫柔嫩艾美耳球虫早熟株和毒株的细胞免疫反应

AA肉鸡雏鸡分别经口免疫柔嫩艾美耳球虫毒株早熟株，用免疫组化ABC法染色检测小肠、盲肠扁桃体、脾脏中CD4^ 、CD8^ T淋巴细胞动态变化；用淋巴细胞转化实验MTT法检测T淋巴细胞活性。结果表明：球虫免疫鸡后，CD4^ T淋巴细胞在一次免疫后迅速增殖，第6天达到第一峰，免疫柔嫩艾美耳球虫毒株的鸡盲肠与脾脏中CD4^ T淋巴细胞占所有淋巴细胞百分率分别达到38％和44％，免疫早熟株的鸡盲肠与脾脏中CD4^ T淋巴细胞占所有淋巴细胞百分率分别达到36％和43％，而二次免疫后和对照相比很少有显著差异。CD8^ T淋巴细胞在一次免疫后比CD4^ T增殖速度慢，第9天达到第一峰。免疫柔嫩艾美耳球虫毒株的鸡在此日盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到37％和47％，免疫早熟株的鸡在此日盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到36％和48％，二次免疫后迅速大量增殖，免疫柔嫩艾美耳球虫毒株的鸡在二免后第2天盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到39％和50％．免疫柔嫩艾美耳球虫早熟株的鸡在二免后第2天盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到37％和50％。且CD8^ T淋巴细胞总体水平比CD4^ T淋巴细胞多。盲肠扁桃体中T细胞的增殖速度比其他组织更快。免疫早熟株的鸡与免疫毒株的鸡肠道黏膜中的CD4^ 、CD8^ T淋巴细胞变化基本一致。一次免疫鸡比未免疫对照T淋巴细胞活性显著升高；进行二免的鸡免疫后第一、二、三周T淋巴细胞活性均比未进行二免的鸡显著升高；毒株免疫鸡T淋巴细胞活性大多与早熟株免疫鸡无8显著差异。     

Dendritic cell-induced memory T cell activation in nonlymphoid tissues

Secondary lymphoid organs are dominant sites of T cell activation, although many T cells are subsequently retained within peripheral tissues. Currently, these nonlymphoid compartments are viewed as sites only of effector T cell function, without the involvement of renewed induction of immunity via the interactions with professional antigen-presenting cells. We describe a method of reactivation of herpes simplex virus to examine the stimulation of tissue-resident T cells during secondary challenge. The results revealed that memory CD8+ T cell responses can be initiated within peripheral tissues through a tripartite interaction that includes CD4+ T cells and recruited dendritic cells. These findings lend evidence for the existence of a sophisticated T cell response mechanism in extra-lymphoid tissues that can act to control localized infection.     

Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.     

Defective CD8 T cell memory following acute infection without CD4 T cell help

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.     

The influence of allogeneic cells on the human T and B cell repertoire

Clinical transplantation is often complicated by rejection episodes, in which the immune system of the recipient reacts to the foreign transplantation (HLA) antigens on the graft. This immune response includes humoral and cellular components. In the first, B lymphocytes form antibodies to the HLA alloantigens. In the second, CD8+ T lymphocytes recognize and react to HLA class I antigens, and CD4+ T cells react to HLA class II antigens. The frequency and severity of these rejection episodes can be diminished by immunosuppressive drugs, HLA matching between donor and recipient, and immune modulation by blood transfusion. Effective HLA matching between donor and recipient is not always possible and often not necessary. Insight into the factors that influence the T and B cell repertoire after blood transfusion might lead to new approaches to improve graft survival.     

Self-nonself discrimination by T cells

The alpha beta T cell receptor (TCR) recognizes antigens that are presented by major histocompatibility complex (MHC)-encoded cell surface molecules by binding to both the antigen and the MHC molecules. Discrimination of self from nonself antigens and MHC molecules is achieved by negative and positive selection of T cells in the thymus: potentially harmful T cells with receptors that bind to self antigens plus self MHC molecules are deleted before they can mount immune responses. In contrast, the maturation of useful T cells with receptors that bind foreign antigens plus self MHC molecules requires the binding of their receptor to MHC molecules on thymic epithelium in the absence of foreign antigen. The binding of the TCR to either class I or class II MHC molecules directs differentiation of the selected cells into either CD4-8+ (killer) or CD4+8- (helper) T cells, respectively.     

Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function

CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.     

A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice.

The development of an immunodeficiency syndrome of mice caused by a replication-defective murine leukemia virus (MuLV) is paradoxically associated with a rapid activation and proliferation of CD4+ T cells that are dependent on the presence of B cells. The responses of normal spleen cells to B cell lines that express the defective virus indicated that these lines express a cell surface determinant that shares "superantigenic" properties with some microbial antigens and Mls-like self antigens. This antigen elicited a potent proliferative response that was dependent on the presence of CD4+ T cells and was associated with selective expansion of cells bearing V beta 5. This response was markedly inhibited by a monoclonal antibody specific for the MuLV gag-encoded p30 antigen.     

Development of a human adaptive immune system in cord blood cell-transplanted mice

Because ethical restrictions limit in vivo studies of the human hemato-lymphoid system, substitute human to small animal xenotransplantation models have been employed. Existing models, however, sustain only limited development and maintenance of human lymphoid cells and rarely produce immune responses. Here we show that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/-gammac-/- mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses. This provides a valuable model to study development and function of the human adaptive immune system in vivo.     

猪轮状病毒与传染性胃肠炎病毒核酸免疫研究

将昆明鼠随机分为A,B,C,D4组,各组分别采用含有猪轮状病毒(RV)JL94株VP7基因的重组真核表达质粒pcDNA-VP7,含有猪传染性胃肠炎病毒(TGEV)TH98株N基因的重组真核表达质粒pcDNA-N,pcD-NA-VP7和pcDNA-N、真核表达载体pcDNA3.1(+),肌肉注射3次,每次间隔2周。首次注射前后定期采血,检测血清抗体和外周血淋巴细胞中CD4+,CD8+T细胞数量的变化。A,C组小鼠血清在首免后第14天即可检出针对RVVP7的阳性抗体(P/N≥2.0)。B组小鼠血清在首免后第39天检出针对TGEVN蛋白的阳性抗体(P/N≥2.0)。A,B,C组小鼠在首免后外周血CD4+、CD8+T细胞数量与D组小鼠相比,在不同时间有显著差异(P<0.05),并明显高于D组小鼠。说明猪轮状病毒与传染性胃肠炎病毒核酸免疫后能诱发机体免疫反应。     

Preferential localization of effector memory cells in nonlymphoid tissue

Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.     

The alarmin interleukin-33 drives protective antiviral CD8⁺ T cell responses

Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8(+) T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.     

Selective stimulation of T cell subsets with antibody-cytokine immune complexes

Interleukin-2 (IL-2), which is a growth factor for T lymphocytes, can also sometimes be inhibitory. Thus, the proliferation of CD8+ T cells in vivo is increased after the injection of a monoclonal antibody that is specific for IL-2 (IL-2 mAb), perhaps reflecting the removal of IL-2-dependent CD4+ T regulatory cells (T regs). Instead, we show here that IL-2 mAb augments the proliferation of CD8+ cells in mice simply by increasing the biological activity of preexisting IL-2 through the formation of immune complexes. When coupled with recombinant IL-2, some IL-2/IL-2 mAb complexes cause massive (>100-fold) expansion of CD8+ cells in vivo, whereas others selectively stimulate CD4+ T regs. Thus, different cytokine-antibody complexes can be used to selectively boost or inhibit the immune response.     

含CpG序列PRRSV ORF5基因真核质粒构建及其免疫原性的研究

 【目的】提高猪繁殖与呼吸综合征病毒（PRRSV）基因免疫的效果,构建含CpG基序和PRRSV ORF5的真核重组表达质粒CpG-pVAX1-ORF5。【方法】经酶切鉴定和序列测定,将重组质粒转染COS-7细胞,经间接免疫荧光试验证实CpG-pVAX1-ORF5可表达PRRSV GP5蛋白。免疫SPF小鼠,检测鼠的特异性抗体滴度、脾T淋巴细胞亚群数量（CD4+和CD8+）以及淋巴细胞增殖反应（MTT法）水平。【结果】本试验构建的含CpG基序真核重组表达质粒CpG-pVAX1-ORF5能诱导小鼠产生针对PRRSV的体液免疫与细胞免疫。【结论】CpG-ODN可提高PRRSV基因疫苗的免疫效果。     

Requirement for CD4 T cell help in generating functional CD8 T cell memory

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.