Presence Of Inflammatory Factors Research Articles

Aspirin attenuates the detrimental effects of TNF-α on BMMSC stemness by modulating the YAP-SMAD7 axis

BackgroundBone marrow mesenchymal stem cells (BMMSCs) are commonly used for cell transplantation to treat refractory diseases. However, the presence of inflammatory factors, such as tumour necrosis factor-alpha (TNF-α), at the transplantation site severely compromises the stemness of BMMSCs, thereby reducing the therapeutic effect of cell transplantation. Aspirin (AS) is a drug that has been in use for over a century and has a wide range of effects, including the regulation of cell proliferation, multidirectional differentiation, and immunomodulatory properties of stem cells. However, it is still unclear whether AS can delay the damaging effects of TNF-α on BMMSC stemness.MethodsThis study investigated the effects of AS and TNF-α on BMMSC stemness and the molecular mechanisms using colony formation assay, western blot, qRT-PCR, and overexpression or knockdown of YAP and SMAD7.ResultsThe results demonstrated that TNF-α inhibited cell proliferation, the expression of stemness, osteogenic and chondrogenic differentiation markers of BMMSCs. Treatment with AS was shown to mitigate the TNF-α-induced damage to BMMSC stemness. Mechanistic studies revealed that AS may reverse the damage caused by TNF-α on BMMSC stemness by upregulating YAP and inhibiting the expression of SMAD7.ConclusionAS can attenuate the damaging effects of TNF-α on BMMSC stemness by regulating the YAP-SMAD7 axis. These findings are expected to promote the application of AS to improve the efficacy of stem cell therapy.

Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT6 receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT6 receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.

Mesenchymal stem cells protect against TBI-induced pyroptosis in vivo and in vitro through TSG-6

BackgroundPyroptosis, especially microglial pyroptosis, may play an important role in central nervous system pathologies, including traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs), such as human umbilical cord MSCs (hUMSCs), has been a focus of brain injury treatment. Recently, MSCs have been found to play a role in many diseases by regulating the pyroptosis pathway. However, the effect of MSC transplantation on pyroptosis following TBI remains unknown. Tumor necrosis factor α stimulated gene 6/protein (TSG-6), a potent anti-inflammatory factor expressed in many cell types including MSCs, plays an anti-inflammatory role in many diseases; however, the effect of TSG-6 secreted by MSCs on pyroptosis remains unclear.MethodsMice were subjected to controlled cortical impact injury in vivo. To assess the time course of pyroptosis after TBI, brains of TBI mice were collected at different time points. To study the effect of TSG-6 secreted by hUMSCs in regulating pyroptosis, normal hUMSCs, sh-TSG-6 hUMSCs, or different concentrations of rmTSG-6 were injected intracerebroventricularly into mice 4 h after TBI. Neurological deficits, double immunofluorescence staining, presence of inflammatory factors, cell apoptosis, and pyroptosis were assessed. In vitro, we investigated the anti-pyroptosis effects of hUMSCs and TSG-6 in a lipopolysaccharide/ATP-induced BV2 microglial pyroptosis model.ResultsIn TBI mice, the co-localization of Iba-1 (marking microglia/macrophages) with NLRP3/Caspase-1 p20/GSDMD was distinctly observed at 48 h. In vivo, hUMSC transplantation or treatment with rmTSG-6 in TBI mice significantly improved neurological deficits, reduced inflammatory cytokine expression, and inhibited both NLRP3/Caspase-1 p20/GSDMD expression and microglial pyroptosis in the cerebral cortices of TBI mice. However, the therapeutic effect of hUMSCs on TBI mice was reduced by the inhibition of TSG-6 expression in hUMSCs. In vitro, lipopolysaccharide/ATP-induced BV2 microglial pyroptosis was inhibited by co-culture with hUMSCs or with rmTSG-6. However, the inhibitory effect of hUMSCs on BV2 microglial pyroptosis was significantly reduced by TSG-6-shRNA transfection.ConclusionIn TBI mice, microglial pyroptosis was observed. Both in vivo and in vitro, hUMSCs inhibited pyroptosis, particularly microglial pyroptosis, by regulating the NLRP3/Caspase-1/GSDMD signaling pathway via TSG-6.1Hpvw1WsEdBy8VCZXh5Sc1Video

Yorkie-Cactus (IκBα)-JNK axis promotes tumor growth and progression in Drosophila.

Presence of inflammatory factors in the tumor microenvironment is well-documented yet their specific role in tumorigenesis is elusive. The core inflammatory pathways like the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway are conserved in Drosophila. We induced GFP-marked epithelial tumors by expressing activated oncogenic forms of RasV12 or Yorkie (Yki3SA, mammalian YAP) in scribble deficient cells (scribRNAi, mammalian SCRIB) to study the role of inflammatory factors in tumorigenesis. Similar to RasV12scribRNAi, we found that Yki3SAscribRNAi form invasive neoplastic lethal tumors that induce a systemic inflammatory response. We identified Cactus (Cact, mammalian IκBα), the negative regulator of TLR, as a key player in tumor growth. Cact accumulates in the cytoplasm in Drosophila tumor models, similar to squamous cell carcinoma in mice models and human patients where cytoplasmic IκBα favors oncogenic transformation. Further, cact is transcriptionally upregulated in tumors, and downregulation of Cact affects tumor growth. We investigated if TLR or TNF pathway affect tumor growth through activation of Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). Genetically manipulating levels of TLR components or TNF receptors showed that Cact acts upstream of JNK signaling and regulates JNK via a non-canonical mechanism during tumorigenesis. Further, Hippo coactivator Yki transcriptionally regulates cact expression, and downregulation of Yki or Cact is sufficient to cause downregulation of JNK-mediated signaling that promotes tumorigenesis. Here, we report a link between Hippo, IκBα and JNK signaling that may induce inflammation and innate immune response in tumorigenesis.

Changes in VEGF-related factors are associated with presence of inflammatory factors in carbohydrate metabolism disorders during pregnancy.

The aim of this study was to determine the action of molecules in carbohydrate metabolism disorders during pregnancy. The concentration of different types of cytokines and vascular endothelial growth factor (VEGF) in the plasma were measured in 4 groups of women: Group I, normal pregnancy (n = 10); Group II, patients with gestational DM (n = 12); Group III, pregnant patients with preexisting DM (n = 16); and Group IV, diabetic non-pregnant women (n = 22). The plasma VEGF concentration was significantly higher in the women in Group IV than in other groups (P <0.01). The concentration of the soluble form of the VEGF receptor-1 (sVEGFR-1) was significantly higher in Group I than in other groups (P <0.01). The concentration of soluble form of the VEGF receptor-2 (sVEGFR-2) was significantly lower in Groups I than in other groups (P <0.05). The concentrations of monocyte chemotactic protein-1 (MCP-1) and eotaxin were significantly lower in Group I than in Groups III and IV. The levels of interleukin (IL)-8, IL-6, and tumor necrosis factor-α (TNF-α) were significantly higher in Group I than in Group IV. Both the VEGF-related molecules and the Inflammatory cytokines are altered in pregnant women with the carbohydrate metabolism disorders.

Analysis of Genetic Variation in CD40 and CD40L: Relationship with mRNA Relative Expression and Soluble Proteins in Acute Coronary Syndrome.

Acute coronary syndrome (ACS) can be triggered by the presence of inflammatory factors which promote the activation of immune cells by costimulatory molecules such as CD40 and its ligand CD40L. Environmental and genetic factors are involved in the etiology of the ACS. The aim of this study was to explore the gene and protein expression associated with CD40 and CD40L genetic variants in ACS patients from the western Mexican population. A total of 620 individuals from western Mexico were recruited: 320 ACS patients and 300 individuals without a history of ischemic cardiopathy were evaluated. The genotype was determined using TaqMan SNP genotyping assays. CD40 and CD40L expressions at the mRNA level were quantified using TaqMan Gene Expression Assays. Soluble protein isoforms were measured by enzyme-linked immunosorbent assay. We did not find evidence of association between CD40 (rs1883832, rs4810485, and rs11086998) and CD40L (rs3092952 and rs3092920) genetic variants and susceptibility to ACS, although rs1883832 and rs4810485 were significantly associated with high sCD40 plasma levels. Plasma levels of sCD40L can be affected by gender and the clinical spectrum of acute coronary syndrome. Our results do not suggest a functional role of CD40 and CD40L genetic variants in ACS. However, they could reflect the inflammatory process and platelet activation in ACS patients, even when they are under pharmacological therapy. Due to the important roles of the CD40-CD40L system in the pathogenesis of ACS, longitudinal studies are required to determine if soluble levels of CD40 and CD40L could be clinically useful markers of a recurrent cardiovascular event after an ACS.

Ginsenoside Rd inhibits IL-1β-induced inflammation and degradation of intervertebral disc chondrocytes by increasing IL1RAP ubiquitination.

Many compounds of ginsenosides show anti-inflammatory properties. However, their anti-inflammatory effects in intervertebral chondrocytes in the presence of inflammatory factors have never been shown. Increased levels of pro-inflammatory cytokines are generally associated with the degradation and death of chondrocytes; therefore, finding an effective and nontoxic substance that attenuates the inflammation is worthwhile. In this study, chondrocytes were isolated from the nucleus pulposus tissues, and the cells were treated with ginsenoside compounds and IL-1β, alone and in combination. Cell viability and death rate were assessed by CCK-8 and flow cytometry methods, respectively. PCR, western blot, and immunoprecipitation assays were performed to determine the mRNA and protein expression, and the interactions between proteins, respectively. Monomeric component of ginsenoside Rd had no toxicity at the tested range of concentrations. Furthermore, Rd suppressed the inflammatory response of chondrocytes to interleukin (IL)-1β by suppressing the increase in IL-1β, tumor necrosis factor (TNF)-α, IL-6, COX-2, and inducible nitric oxide synthase (iNOS) expression, and retarding IL-1β-induced degradation of chondrocytes by improving cell proliferation characteristics and expression of aggrecan and COL2A1. These protective effects of Rd were associated with ubiquitination of IL-1 receptor accessory protein (IL1RAP), blocking the stimulation of IL-1β to NF-κB. Bioinformatics analysis showed that NEDD4, CBL, CBLB, CBLC, and ITCH most likely target IL1RAP. Rd increased intracellular ITCH level and the amount of ITCH attaching to IL1RAP. Thus, IL1RAP ubiquitination promoted by Rd is likely to occur by up-regulation of ITCH. In summary, Rd inhibited IL-1β-induced inflammation and degradation of intervertebral disc chondrocytes by increasing IL1RAP ubiquitination.

The IL-2/Anti-IL-2 Complex Attenuates Cardiac Ischaemia-Reperfusion Injury Through Expansion of Regulatory T Cells

Background/Aims: Regulatory T cells (Tregs) can suppress immunologic damage in myocardial ischaemia/reperfusion injury (MIRI), however, the isolation and ex vivo expansion of these cells for clinical application remains challenging. Here, we investigated whether the IL-2/anti-IL-2 complex (IL-2C), a mediator of Treg expansion, can attenuate MIRI in mice. Methods: Myocardial I/R was surgically induced in male C57BL/6 mice, aged 8-10 weeks, that were randomly assigned to 1) sham group (Sham), 2) Phosphate Buffered Saline (PBS), 3) IL-2-anti-IL-2 Ab complex (IL-2C), or 4) sham group, 5) PBS, 6) IL-2C after MIRI, or 7) IL-2C, 8) IL-2C+anti-CD25 mAbs, or 9) IL-2C; 10) IL-2C+anti-TGF-β1 mAbs, 11) IL-2C+anti-IL-10 mAbs. The following parameters were measured at different time points: infarct area, myocardial apoptosis, splenocytes, the inhibitory function of Tregs, and presence of inflammatory factors. In addition, immunohistochemistry analysis was performed. Results: We observed that Tregs were activated in response to MIRI. IL-2C administered before MIRI induced Treg expansion in both spleen and heart, attenuated Th1 and Th17 cell numbers, improved myocardial function, and attenuated both infiltration of inflammatory cells and apoptosis after MIRI. Furthermore, IL-2C administration reduced expression of inflammatory cytokines in the heart and attenuated proliferation of splenic cells. Depletion of Tregs with anti-CD25 mAb abrogated the beneficial effects of IL-2C. However, IL-2C–mediated myocardial protection was not dependent on either IL-10 or TGF-β. In addition, IL-2C administration after MIRI did not reduce infarct area, but did improve myocardial function slightly and reduced myocardial fibrosis. Conclusion: Our results demonstrate that IL-2C–induced Treg expansion attenuates MIRI and improves myocardial recovery in vivo, suggesting that IL-2C is a promising therapeutic target for myocardial IRI.

Examining the properties and therapeutic potential of glial restricted precursors in spinal cord injury.

In the aftermath of spinal cord injury, glial restricted precursors (GRPs) and immature astrocytes offer the potential to modulate the inflammatory environment of the injured spinal cord and promote host axon regeneration. Nevertheless clinical application of cellular therapy for the repair of spinal cord injury requires strict quality-assured protocols for large-scale production and preservation that necessitates long-term in vitro expansion. Importantly, such processes have the potential to alter the phenotypic and functional properties and thus therapeutic potential of these cells. Furthermore, clinical use of cellular therapies may be limited by the inflammatory microenvironment of the injured spinal cord, altering the phenotypic and functional properties of grafted cells. This report simulates the process of large-scale GRP production and demonstrates the permissive properties of GRP following long-term in vitro culture. Furthermore, we defined the phenotypic and functional properties of GRP in the presence of inflammatory factors, and call attention to the importance of the microenvironment of grafted cells, underscoring the importance of modulating the environment of the injured spinal cord.

Study of the relationship between mononuclear inflammatory infiltrate and Ki-67 and basement membrane and extracellular matrix protein expression in radicular cysts.

To evaluate the relationship between mononuclear inflammatory infiltrate and the expression of a proliferative immunomarker (Ki-67) as well as to evaluate basement membrane and extracellular matrix proteins (laminin and collagen type IV) in radicular cysts and dentigerous cysts (DC). Immunohistochemical analyses were performed in heavily inflamed radicular cysts (HIRC), slightly inflamed radicular cysts (SIRC) and DC (n=20) using Ki-67 (Dako(®) , 1:50), anticollagen type IV (DBS(®) , 1:40) and antilaminin (DBS(®) , 1:20). The data were analysed using anova/Tukey's test (Ki-67) and Kruskal-Wallis/Dunn's test (collagen type IV and laminin) (P<0.05). The immunoexpression of Ki-67 was significantly greater in the SIRC group compared with the HIRC and DC (P=0.0040). Likewise, the immunoexpression of collagen type IV in the basement membrane of the SIRC group was significantly more continuous (P=0.0475) than in the HIRC group. DC had significantly less collagen type IV in extracellular matrix immunoexpression than HIRC and SIRC (P=0.0246). Laminin was absent in the basement membrane in the SIRC and DC groups, and the extracellular matrix of the HIRC was weak and punctate. The presence of inflammatory factors in the radicular cyst wall modified the expression of proliferation factors in the epithelial lining and the expression of collagen type IV and laminin in the basement membrane, but did not modify extracellular matrix behaviour in radicular cysts.

Hypothalamic innate immune reaction in obesity.

Findings from rodent and human studies show that the presence of inflammatory factors is positively correlated with obesity and the metabolic syndrome. Obesity-associated inflammatory responses take place not only in the periphery but also in the brain. The hypothalamus contains a range of resident glial cells including microglia, macrophages and astrocytes, which are embedded in highly heterogenic groups of neurons that control metabolic homeostasis. This complex neural-glia network can receive information directly from blood-borne factors, positioning it as a metabolic sensor. Following hypercaloric challenge, mediobasal hypothalamic microglia and astrocytes enter a reactive state, which persists during diet-induced obesity. In established mouse models of diet-induced obesity, the hypothalamic vasculature displays angiogenic alterations. Moreover, proopiomelanocortin neurons, which regulate food intake and energy expenditure, are impaired in the arcuate nucleus, where there is an increase in local inflammatory signals. The sum total of these events is a hypothalamic innate immune reactivity, which includes temporal and spatial changes to each cell population. Although the exact role of each participant of the neural-glial-vascular network is still under exploration, therapeutic targets for treating obesity should probably be linked to individual cell types and their specific signalling pathways to address each dysfunction with cell-selective compounds.

Relapse of melanoma after successful adoptive T‐cell therapy: escape through inflammation‐induced phenotypic melanoma cell plasticity

Advanced stage melanomas are refractory to most available therapies including recently approved targeted therapies. This is also true for most biological (IFN-a or IL-2) treatments and therapy involving adoptive transfer of melanoma-reactive T cells (de Souza et al., 2012). A number of mechanisms have been proposed to explain the lack of T-cell functional activity in vivo. Some of these mechanisms include emergence of antigen-loss tumor variants, induction of immune inhibitory molecules such as CTLA4 or PD1 and induction of T-reg (regulatory) cells or myeloid-derived suppressor cells (MDSC) or presence of immune-suppressive cytokines such as TGF-b or IL-10 (Grivennikov et al., 2010). A number of environmental factors can further contribute to genetic instability and induce epigenetic changes of progressing heterogeneous tumors. Presence of inflammatory factors at the tumor site can cause selection of preexisting tumor cell variants resulting in preferential growth of antigen-negative tumor variants or tumor cells that have lost MHC-class I molecules (Khong and Restifo, 2002). Immune editing or alterations of tumor antigens due to immune pressure can also be one of the reasons for lack of T-cell-mediated tumor cell death in vivo (Singh and Paterson, 2007). In clinical trials, adoptive cell therapies (ACT) with melanoma-reactive tumor-infiltrating lymphocytes (TILs) or polyclonal T cells engineered to express chimeric antigen receptor (CAR) with re-directed specificity to melanoma have shown great promise with dramatic regression of bulky tumors (Robbins et al., 2011). However, in most patients, initial regression of tumor cells was followed by appearance of new lesions with therapy resistant melanoma cells (Robbins et al., 2011). Until now, the exact nature of ACT-related tumor resistance and the cause of emergence of antigen-negative melanoma cells were largely unknown. In the current edition of Nature, Landsberg et al. describe a novel mechanism of T-cell-induced loss of melanocytic antigens as a possible cause of tumor cell resistance to ACT. To demonstrate therapy resistance, the authors have used a previously published genetically engineered hepatocyte growth factor (Hgf)-Cdk4 mouse melanoma model and anti-gp100-specific CTLs obtained from a TcR transgenic pmel-1 (gp100) mouse model. TNF-a, a proinflammatory cytokine predominantly secreted by activated T cells caused down-modulation of gp100 antigen expression on the mouse melanoma cells resulting in loss of recognition by anti-gp100-specific CTLs used in ACT. TNF-a also down-modulated pigmentrelated gene expression and tyrosinaserelated protein (TRP)-2 on melanoma cells. Interestingly, the pro-inflammatory environment of TNF-a did not downmodulate the expression of non-melanocytic antigens. On the contrary, there was an increased expression of nerve growth factor receptor (NGFR) on melanoma cells. Down-modulation of gp100 expression was reversible when the activity of TNF-a was neutralized or the resistant tumor cells were re-transplanted into a normal mouse lacking an inflammatory environment. The mechanism of non-genetic reversible antigen down-modulation is novel and has not been described before. This is in contrast to other genetic heterogeneityand immunoselection-related mechanisms described earlier. Understanding inflammation-induced plasticity and the non-genetic heterogeneity of melanoma cells are critical for the development of new therapeutic strategies for melanoma. The authors then corroborated their mouse studies using human melanoma cell lines where they report similar down-modulation of gp100 and MART1/Melan-A expression in the presence of TNF-a. Similar to mouse studies, human melanoma cell lines also showed up-regulation of NGFR expression in the presence of TNF-a. This was confirmed in melanoma patients’ tumor tissue sections with abundant infiltrating immune cells further supporting the clinical relevance of the above findings. The results of Landsberg et al. have important clinical implications if the phenotypic plasticity of melanoma cells in an inflammatory microenvironment is validated in a larger cohort of patients with melanoma after ACT. Down-modulation of gp100 expression and concurrent up-regulation of NGFR expression of melanoma cells in an inflammatory environment raises the possibility of using ACT with a cocktail of CAR-engineered T cells with dual or multiple specificities to target more than one melanoma antigen to ensure complete regression of tumor lesions. For this, a personalized approach of analyzing melanoma antigen expression on tumor cells before and after ACT therapy will be essential for the selection of CARengineered T cells with defined tumor antigen specificity. The proposed approach may enhance the long term disease-free survival of patients with metastatic melanoma.

The dual (activating/suppressive) effect of extracellular TatHIV-1 is driven by the infalmmatory microenvironment of infected lymphoid foci

It has been shown that HIV-1 infects activated but not resting CD4+ T cells [1] and that CPE induced by viral replication together with the immunosuppressive effect triggered by extracellular Tat protein [2] account for the decrease of CD4+ T cell count in infected patients. In lymphoid foci, dependent on the level of viral infection, the stromal microenvironment surrounding immune cells could include, together with extracellular Tat [3] and circulating antiviral IFN-α, inflammatory innate factors such as ATP and derivatives released by CPE-derived dead cells. We show that, according to its concentration and the presence of inflammatory factors (IFN-α, ATP and ATP-derivatives), Tat protein may exert either an activation with enhanced production of IL2 or an immune suppression of stimulated CD4+ T cells subpopulations. The double-edged sword of Tat activity on CD4+ T cells could account for its immunopathogenic effects both at the early stage of infection (by allowing CD4+ T cells activation and viral replication) and at late stages (by inducing immuosuppression, source of opportunistic infections). Indications for targeting Tat protein by therapeutic vaccines in subgroups of HIV-1 infected patients will be discussed.

Abstract SY19-01: Identifying and overcoming immune barriers at the level of the tumor microenvironment

Abstract Immunotherapeutic approaches for the treatment of melanoma, such as tumor antigen-based vaccines, can frequently boost immune responses as measured in the peripheral blood. However, clinical responses as measured by tumor shrinkage have been observed in only a minority of patients. This observation has prompted careful analysis of the tumor microenvironment to probe for biologic correlates to clinical response and also to identify mechanisms of tumor resistance. Patients with advanced melanoma treated on two different vaccine platforms had pretreatment tumor biopsies analyzed by Affymetrix gene expression profiling. Supervised hierarchical clustering was performed based on favorable or unfavorable clinical outcome. An expanded bank of tumors was also analyzed to increase the sample size and better understand gene patterns that segregate into subtypes. Two major categories of melanoma metastases have been observed. One subgroup of patients has an inflamed phenotype that includes expression of chemokines, T cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immune suppressive mechanisms may dominantly inhibit antitumor T cell function in those patients. In addition, absence of B7 expression suggests that classical T cell anergy also may be operational. Preclinical experiments have confirmed a critical role for all 4 of these mechanisms in limiting antitumor T cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic. These include IDO inhibitors, anti-PD-1 mAbs, and approaches to deplete CD25+ Tregs. A second subset of patients is represented by tumors which are noninflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T cell migration into tumor sites. Experimental strategies to augment T cell migration can have important antitumor effects in preclinical models. Finally, the presence of inflammatory factors was associated with a type I IFN transcriptional signature, and murine experimental models have confirmed a critical role for type I IFN signaling in mediating innate immune “sensing” of a growing tumor in vivo. Our results confirm that molecular profiling of melanoma metastases may be useful as a predictive biomarker for response to melanoma vaccines. In addition, specific features identified in defined subsets of patients offer new therapeutic strategies based on overcoming resistance to immune destruction at the level of the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2011-SY19-01

Bystander Virus Infection Prolongs Activated T Cell Survival

In animals, T cells often die rapidly after activation, unless activation occurs in the presence of inflammatory factors. To understand how such activated cells survive to participate in immune responses, we studied the effects of viral infection on T cells responding to an unrelated superantigen. Normal T cells activated by superantigen in uninfected mice died as a result of their activation, whereas T cells that were activated during vaccinia infection survived longer in vivo and in culture. This bystander effect of viral infection on activated T cells was independent of effects on the magnitude of the initial T cell response, on induction of Bcl-2 and Bcl-x, on T cell proliferation, and on Fas killing. The failure of such effects to predict the fate of activated T cells in vivo indicates that virus infections shape T cell responses via mechanisms that differ from those described previously. These mechanisms may contribute to the ability of viral infections to induce autoimmunity.