Immunotherapy with Agonistic Anti-CD137： Two Sides of a Coin

CD137 (4-1BB),a member of the TNF receptor superfamily,is an inducible T cell costimulatory receptorprimarily expressed on activated CD4~+ and CD8~+ T cells.Agonistic monoclonal antibodies (mAbs) against CD137greatly enhance T cell-mediated immune responses against many types of tumors and viruses.Surprisingly,theseagonists also showed therapeutic effects in several autoimmune diseases.These findings suggest that in differentdisease environments,CD137 engagement with agonist mAb in vivo can diametrically modulate immuneresponse outcomes.Therefore,CD137 agonists represent a promising immunotherapeutic approach to a widearray of disparate immune disorders.However,CD137's potency in modulating immune response necessitatescaution when targeting CD137 clinically.Cellular & Molecular Immunology.2004;1(1):31-36.     

Immunotherapy of cancer employing adoptiveT cell transfer

Adoptive T cell immunotherapy of cancer involvespassive administration of lymphoid cells from onehost to another, or back to itself in order to trans fer tumor immunity for cancer treatment. It wasfirst realized more than twenty years ago that adop tive immunotherapy may be feasible to treat humanmalignancies. However, the early form of thispractice was quite simple. It could be as easy as astraightforward blood cell transfer. The apparentinefficiency of antitumor immune respon…     

Early Reconstitution of NK and γδ T Cells and Its Implication for the Design of Post-Transplant Immunotherapy

Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Natural killer (NK) cells and γδ T cells reconstitute early after allo-HSCT, contribute to tumor immunosurveillance via major histocompatibility complex–independent mechanisms and do not induce graft-versus-host disease. Here we performed a quantitative and qualitative analysis of the NK and γδ T cell repertoire in healthy individuals, recipients of HLA-matched sibling or unrelated donor allo-HSCT (MSD/MUD-HSCT) and umbilical cord blood-HSCT (UCB-HSCT). NK cells are present at high frequencies in all allo-HSCT recipients. Immune reconstitution (IR) of vδ2⁺?cells depended on stem cell source. In MSD/MUD-HSCT recipients, vδ2⁺?comprise up to 8% of the total lymphocyte pool, whereas vδ2⁺?T cells are barely detectable in UCB-HSCT recipients. Vδ1⁺?IR was driven by CMV reactivation and was comparable between MSD/MUD-HSCT and UCB-HSCT. Strategies to augment NK cell mediated tumor responses, similar to IL-15 and antibodies, also induced vδ2⁺?T cell responses against a variety of different tumor targets. Vδ1⁺?γδ T cells were induced less by these same stimuli. We also identified elevated expression of the checkpoint inhibitory molecule TIGIT (T cell Ig and ITIM domain), which is also observed on tumor-infiltrating lymphocytes and epidermal γδ T cells. Collectively, these data show multiple strategies that can result in a synergized NK and γδ T cell antitumor response. In the light of recent developments of low-toxicity allo-HSCT platforms, these interventions may contribute to the prevention of early relapse.     

Function of Helper T Cells in the Memory CTL-mediated Anti-tumor Immunity

CD4 Tcellsarerequiredforthegenerationandmainte nanceofcytolyticCD8 Tcellsandareessentialforthe generationofbothcellularandhumoralimmuneresponses. However,thecontributionofCD4 Tcellstothemainte nanceofanti tumorimmunityisstillthesubjectofintense investig…     

Type 1 CD8^＋ T Cells are Superior to Type 2 CD8^＋ T Cells in Tumor Immunotherapy due to Their Efficient Cytotoxicity, Prolonged Survival and Type 1 Immune Modulation

CD8^＋ cytotoxic T （Tc） cells play a crucial role in host immune responses to cancer, and in this context, adoptive CD8^＋ Tc cell therapy has been studied in numerous animal tumor models. Its antitumor efficacy is, to a large extent, determined by the ability of Tc cells to survive and infiltrate tumors. In clinical trials, such in vitro-activated T cells often die within hours to days, and this greatly limits their therapeutic efficacy. CD8^＋ Tc cells fall into two subpopulations based upon their differential cytokine secretion. In this study, we in vitro generated that ovalbumin （OVA）-pulsed dendritic cell （DCovA）-activated CD8^＋ type 1 Tc （Tcl） cells secreting IFN-T, and CD8^＋ type 2 Tc （Tc2） cells secreting IL-4, IL-5 and IL-10, which were derived from OVA-specific T cell receptor （TCR） transgenic OT I mice. We then systemically investigated the in vitro and in vivo effector function and survival of Tcl and Tc2 cells, and then assessed their survival kinetics after adoptively transferred into C57BL/6 mice, respectively. We demonstrated that, when compared to CD8^＋ Tc2, Tcl cells were significantly more effective in perforin-mediated cytotoxicity to tumor cells, had a significantly higher capacity for in vivo survival after the adoptive T cell transfer, and had a significantly stronger therapeutic effect on eradication of well-established tumors expressing OVA in animal models. In addition, CD8^＋ Tcl and Tc2 cells skewed the phenotype of CD4^＋ T cells toward Thl and Th2 type, respectively. Therefore, the information regarding the differential effector function, survival and immune modulation of CD8^＋ Tcl and Tc2 cells may provide useful information when preparing in vitro DC-activated CD8^＋ T cells for adoptive T cell therapy of cancer.     

Distinct Pattern of Human Vδ1 γδ T Cells Recognizing MICA

γδT cells represent one unique recognition pattern,the limited recognition,which distinguishes from the specificrecognition for αβT cells and pattern recognition for macrophages.Vδ1 γδT cell is the major subset of human γδT cells,which predominates in mucosal tissue including the intestinal epithelia.Presently,a few antigens thathuman Vδ1TCR can recognize have been identified.Among them,MHC class I chain-related molecules A (MICA)have been studied most intensively.Besides Vδ1TCR,MICA is also the ligand of NKG2D,a C-type lectin-likeactivating immunoreceptor.In human,only Vδ1 cells can simultaneously express both types of receptors of MICAwhile NK cells,αβT cells and other subsets of γδT cells likewise express NKG2D.Although the precisemechanisms are still enigmatic,this distinct pattern of Vδ1 cells recognizing MICA predicts unique biologicalsignificance of Vδ1 cells in immune defense.Recent years,some progresses have been made in this issue.In thisreview we summarize the related reports and put forward some novel views based on our group's studies.Cellular& Molecular Immunology.2005;2(4):253-258.     

The Role of Innate Immune Cells in the Response of Heat-Treated Mycobacterium tuberculosis （M.tb） Antigens Stimulating PBMCs

The proliferation response of γδT cells to the antigen from heat-treated Mycobacterium tuberculosis H37Ra(M.tb Ag)was used as a good model in γδT cell research.From preliminary research it is found that activatedNK cells positively elevated γδT cells proliferation after simulating PBMCs with M.tb Ag.To investigatedifferent behaviors of NK cells,γδNKT cells,γδT cells and relationships between these cell subsets,activationand proliferation of different cell subsets of PBMCs in response to M.tb Ag were analyzed.We demonstratedthat NK cells,γδNKT cells and γδT cells could be activated after stimulation with M.tb Ag.γδNKT cells and γδTcells proliferated while the number of NK cells decreased after 11 day-simulation with M.tb Ag.Meanwhile,atthe early time of stimulation the cytotoxicity of PBMCs was enhanced.Cellular & Molecular Immunology.2004;1(6):467-470.     

The Plasticity of γδT Cells: Innate Immunity, Antigen Presentation and New Immunotherapy

Several signals influence dendritic cell (DC) functions and consequent the immune responses to infectious pathogens. Our recent findings provide a new model of intervention on DCs implicating human γδ T cell stimuli. Vγ9Vδ2 T cells represent the major subset of circulating human γδ T cells and can be activated by non-peptidic molecules derived from different microorganisms or abnormal metabolic routes. With activated-Vγ9Vδ2 T cell co-culture, immature DCs acquire features of mature DCs, such as increasing the migratory activity, up-regulating the chemokine receptors, and triggering the Thl immune response. Similar to the NK-derived signals, DC activation is mediated by soluble factors as well as cell-to-cell contact. Many non-peptidic molecules including nitrogen- containing bisphosphonates and pyrophosphomonoester drugs, can stimulate the activity of Vγ9Vδ2 T cells in vitro and in vivo. The relatively low in vivo toxicity of many of these drugs makes possible novel vaccine and immune-based strategies against infectious diseases. Cellular & Molecular Immunology. 2008;5(3):161-170.     

Dangerous allergens: innate immunity,dendritic cells and allergic asthma

Immune responses can be compartmentalized into innate versus adaptive components. This relatively recent dichotomy positioned the innate immune system at the interface between the host and the external environment, and provided a new conceptual framework with which to view allergic diseases, including asthma. Among the cells of the innate immune system, antigen-presenting dendritic cells are now thought to be intimately involved in allergen recognition, as well as modulating allergic immune responses. This review summarizes current thinking regarding the role of dendritic cells in allergic asthma and concludes with a summary of emerging concepts in the field.     

Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells

Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut–liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.     

Dendritic cells modulated by innate immunity improve collagen-induced arthritis and induce regulatory T cells in vivo

Dendritic cells (DCs) mediate interactions between innate and specific immunity and may induce regulatory mechanisms. We investigated the effects of modulated DCs in mice with collagen-induced arthritis (CIA) and tested the responses of cells to induced naturally occurring regulatory T cells. DCs were stimulated or not with DNA or lipopolysaccharide (LPS) for 24 hr. DC maturation was assayed, and then modulated DCs were intraperitoneally injected on day 14 into DBA/1 mice to treat CIA. In addition to arthritis scores and type 2 collagen (CII) response, the induction of CD4(+) CD25(+) T cells was analysed by flow cytometry in peripheral blood and the expression of Foxp3, transforming growth factor (TGF)-beta, interleukin (IL)-10 and cytotoxic T-lymphocyte antigen (CTLA)-4 was quantified. Finally, the expression of indoleamine-2,3-dioxygenase (IDO) was assayed in DCs. In comparison with LPS-stimulated DCs, plasmid-stimulated DCs expressed lower levels of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86 molecules and secreted less IL-12p70, interferon (IFN)-gamma, IL-10 and TNF-alpha, displaying a semi-mature phenotype. Compared with non-stimulated DCs, stimulated DCs improved arthritis scores when injected after immunization, without modifying the T helper type 1 (Th1)/Th2 balance of the immune response against collagen. Stimulated DCs induced markers for regulatory T cells (Foxp3, TGF-beta1 and CTLA-4) in vivo. Only LPS-stimulated DCs expressed IDO, which may explain their better therapeutic efficacy. Regulatory mechanisms were induced using DCs modulated by innate immunity stimulators. Innate immunity mechanisms do not require the presence of the disease-causing antigen, even in T- and B-cell specific diseases. Our results have implications for the treatment of rheumatoid arthritis, an autoimmune disease whose triggering antigen has not been identified, and substantially clarify the role of regulatory T cells in CIA.     

Natural type I interferon-producing cells as a link between innate and adaptive immunity

Type I interferons (IFNs) are promptly produced upon invasion of pathogens, and activate a broad range of effector cells in the innate and adaptive immune system. Lin⁻CD4⁺CD11c⁻ plasmacytoid dendritic cell precursors (plasmacytoid pre-DCs) produce enormous amounts of type I IFNs in response to viruses and CpG DNA, thus corresponding to the previously described but not fully defined natural type I IFN-producing cells (IPCs). Plasmacytoid pre-DCs strongly express toll-like receptor (TLR) 7 and TLR9, in contrast to monocytes, which mainly express TLR1, 2, 4, 5, and 8, suggesting that these two DC precursors recognize different microbial molecules and that they may have developed through different evolutionary trails. Three different stimuli, CpG DNA plus CD40 ligand, interleukin-3 (IL-3), and herpes simplex virus, stimulate plasmacytoid pre-DCs to differentiate into DCs that induce distinct types of T helper cells, i.e., Th1, Th2, and IFN-γ- and IL-10-producing T cells, respectively. The remarkable versatility of plasmacytoid pre-DCs distinguishes them from other cell types in the immune system that have only limited functions, and suggests that these cells may play a key role in integrating the innate and adaptive aspects of various immune responses.     

Th17 T cells: linking innate and adaptive immunity

While the cytokine IL-17 has been cloned and described more than 10 years ago [Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3(6):811-21; Kennedy J, Rossi DL, Zurawski SM, Vega Jr F, Kastelein RA, Wagner JL, et al. Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR+CD4-CD8-T cells. J Interferon Cytokine Res 1996;16(8):611-7], it was only 2 years ago that IL-17 producing T cells have been classified as a new distinct CD4 T cell subset [Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6(11):1123-32] and only in 2006 the molecular mechanisms underlying their differentiation were identified [Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24(2):179-89; Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090):235-8; Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441(7090):231-4]. Since then the literature on IL-17 producing cells has grown steadily and many reviews of the field are already outdated by the time they are published, a fate that no doubt will affect this review as well. In order to avoid too many repetitions we focus this review mainly on publications in 2006 and 2007 and refer to a number of reviews, which cover earlier aspects of Th17/IL-17 biology.     

Heat shock protein and innate immunity

In addition to serving as molecular chaperones,heat shock proteins (HSPs) have been implicated inautoimmune diseases,antigen presentation and tumor immunity.Extensive work in the last 10 years has alsosuggested that HSPs such as Hsp60,Hsp70,Hsp90 and gp96,may be potent activators of the innate immunesystem capable of inducing the production of pro-inflammatory cytokines by the monocyte-macrophage system,and the activation and maturation of dendritic cells via the Toll-like receptor 2 and 4 signal transductionpathways.However,recent evidence suggests that the reported cytokine effects of HSPs may be a result of thecontaminating bacterial cell-wall products.This concise review summarizes the current controversy over therole of HSPs in innate immunity.Cellular & Molecular Immunology.2004;1(4):274-279.     

CD8+ T cell exhaustion in anti-tumour immunity: The new insights for cancer immunotherapy

CD8⁺ T cells play a crucial role in anti-tumour immunity, but they often undergo exhaustion, which affects the anti-tumour activity of CD8⁺ T cells. The effect and mechanism of exhausted CD8⁺ T cells have become the focus of anti-tumour immunity research. Recently, a large number of studies have confirmed that long-term antigen exposure can induce exhaustion. Cytokines previously have identified their effects (such as IL-2 and IL-10) may play a dual role in the exhaustion process of CD8⁺ T cells, suggesting a new mechanism of inducing exhaustion. This review just focuses our current understanding of the biology of exhausted CD8⁺ T cells, including differentiation pathways, cellular characteristics and signalling pathways involved in inducing exhaustion, and summarizes how these can be applied to tumour immunotherapy.     

Plasmacytoid dendritic cells act as the most competent cell type in linking antiviral innate and adaptive immune responses

Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies, pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exatnining the functional and antiviral properties of in vivo pDC plasticity. Cellular ＆ Molecular Immunology. 2005;2（6）：411- 417.