innate CD8(+) T cells

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Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

FigUre 5 | Continued representative view of the inKt/innate Cd8(+) t-cell axis hypothesis in chronic myeloid leukemia (CML). We propose the following scenario in CML: (a) steady state/healthy situation. Normal hematopoietic stem cells (HSC) generate normal immune cells. Antigens are presented via the CD1d molecule by dendritic cells (DCs) to iNKT cells. We propose that activated iNKT cells produce IL-4 but the possibility of a T-cell receptor (TCR)-independent mechanism for IL-4 secretion cannot be ruled out. IL-4 is thought to take part with IL-15 in the development/homeostasis of innate CD8( +) T cells. iNKT and innate CD8(+) T cells produce IFN-γ and perforin in response to the innate-like IL-12  + IL-18 stimulation. (B) Chronic phase of CML. Leukemic stem cells (LSC) produce modified immune cells bearing BCR–ABL translocation, including DCs. Impaired CD1d antigen presentation by DCs results from activation of the Rho/Rock pathway via the DH-PH domain of the ABL part of BCR–ABL. iNKT cell development/stimulation is thereby impaired, especially in terms of promyelocytic leukemia zinc-finger factor (PLZF) expression and IL-4 production. Consequently, we surmise that the innate CD8( +) T subset is defective in number and function. (C) Restoration of the iNKT/innate CD8(+) T-cell axis by therapies. IFN- α therapy is thought to help restoring DCs and innate CD8(+) T cells as well as other unidentified cells. Tyrosine kinase inhibitor (TKI) therapies targeting the ABL tyrosine kinase domain clear/control the generation of LSC and abnormal immune cells, including DCs. Fasudil therapy, combined with TKI, restores the CD1d presentation by DCs to iNKT cells and is one possible mechanism to restore the iNKT/innate CD8( +) T-cell axis.
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en fr Characterization of innate memory CD8 T cells using new biomarkers Identification de nouveaux biomarqueurs permettant la caractérisation des lymphocytes T CD8 mémoires innés

Acide DésoxyRibonucléique AutoImmune REgulator Activator Protein 1 Antigen Presenting Cells Altered Peptide Ligands Acide RiboNucléique messager Adénosine Triphosphate Complexe Majeur d’[r]

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The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia

The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia

The finding that CML, at diagnosis is closely associated with a profound quantitative and functional deficiency in the innate CD8(+), T cell pool is in line with our hypothesis that this new subset may be involved during tumorigenesis in humans. This assumption was earlier based on our demonstration of termi- nally differentiated effector features of innate CD8(+) T cells in humans, such as rapid production of IFN-γ and induction of cytolytic function upon stimulation in vitro. In the present study, our revelation of the profound impact of CML on these potential antitumoral functions of innate CD8(+) T cells, together with those of NK (see Figure S2 in Supplementary Material) and iNKT cells ( 22 , 27 ), support a role in cancer immune surveillance of innate CD8(+) T cells analogous to the two other innate cell pools. Even though these findings corroborate the concept that innate CD8(+) T cells, like iNKT cells, may act against tumors in a TCR-independent and NK-like manner, the possibility that these cells recognize leukemia cells cannot be excluded and deserves further investigation.
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Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria in the mouse

Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria in the mouse

and that such secretion partially contributes to the protective recall response [29,30]. Finally, several studies have demonstrated that innate cells such as neutrophils and inflammatory monocytes expressing the myeloid marker Ly-6C -also defined as TNF/NO- producing DCs (Tip-DCs)- produce antimicrobial mediators known to be critical for pathogens clearance [31,32]. Therefore, we characterized the composition of the OT-I clusters induced 6 hours after the challenge infection and looked for the presence of the innate immune cell types and effector functions described above. Spleens sections from Wt L.m-OVA challenged mice (6 h) were stained for the expression of B220, CD8, CD4 (Figure 6A); CD11c, L.m antigens (Figure 6C) and CD8, IFN-c (Figure 6D). Attention was focused on the clusters of memory OT-I cells. Data show that these clusters were massive (.100 m m), composed of both CD4 + and CD8 + T cells (but not B cells) and were usually found around L.m-infected CD11c + cells, similar to what was recently described during the secondary challenge infection against Toxoplasma gondii in LNs [18]. Most interestingly, we observed both on tissue sections and by flow cytometry an intense IFN-c secretion by memory OT-I cells in these clusters that we therefore named ‘‘effector clusters’’ (Figure 6D). Although we were unable to detect CCL3 on sections, likely due to a low expression of this chemokine, we did observe CCL3 secretion in memory OT-I cells by flow cytometry. Interestingly, CCL3 expression was always observed in IFN-c secreting OT-I cells (Figure 7). As IFN-c secretion by memory OT-I cells was only observed in these effector clusters, we concluded that OT-I cells secreting CCL-3 were also localized in these clusters. To determine if neutrophils were also present there, we took advantage of the GFP- expressing lys-M knock-in mouse in which neutrophils express high amounts of GFP [33]. Massive and local accumulations of neutrophils were indeed found in these
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Involvement of CD8+ T Cells in Multiple Sclerosis

Involvement of CD8+ T Cells in Multiple Sclerosis

the blood of MS patients has also been evidenced, suggesting a specific involvement in the disease ( 32 ). Recently, it has been shown that more than 80% of these cells are mucosal-associated invariant T (MAIT) cells. MAIT cells are a subset of innate effector memory T cells bearing a semi-invariant TCR (Vα7.2-Jα33/12/20) in humans ( 77 – 82 ). They are restricted to the MHC class-I related protein I (MR1) and have antimicro- bial properties both in vitro and in vivo ( 83 – 86 ). Although they have been correlated with various autoimmune diseases ( 87 – 90 ), their implication, especially in MS ( 32 , 91 , 92 ), remain elusive. MAIT cells are present in the CNS of MS patients, but at very low frequencies compared to in the blood ( 92 – 94 ). This argues against a particular implication of this IL-17-producing CD8 +
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A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

which one would have increased chances of being successful once applied to humans. dendritiC CeLL inFeCtion WitH HsV-2 Dendritic cells are professional antigen presenting cells that play fundamental roles at establishing and regulating immune responses at the interface of innate and adaptive immunity ( 63 ). DCs are distributed within organs and tissues in the body and also located in the periphery, in tissues such as the skin and genital tract where they detect, capture, and process microbes and their antigens ( 64 ). Upon antigen capture, these cells migrate to the draining lymph nodes and display peptide fragments obtained from these microorganisms to antigen-specific T cells ( 63 , 65 ). This DC–T  cell interaction will educate T  cells based on the integration of signals derived from membrane-bound and soluble molecules presented and secreted by DCs ( 66 , 67 ). Attributes developed in T  cells include the capacity to kill infected cells, secrete modulatory cytokines and regulate the functions of other immune cells, which will ultimately define the overall profile of the immune response elicited against an antigen ( 68 ). Therefore, many pathogens have evolved molecular mechanisms to hamper the function of DCs ( 69 – 71 ).
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IL-12 Signaling Contributes to the Reprogramming of Neonatal CD8+ T Cells

IL-12 Signaling Contributes to the Reprogramming of Neonatal CD8+ T Cells

a set of 23 genes, overexpressed in naïve neonatal CD8 + T cells that were specifically repressed by TCR/IL-12 stimulation (Figure 5B). These genes were associated with the innate immune response (Figure 5C), such as the metalloprotease gene MPO and DEFA4, associated with antimicrobial activity and migration into intestinal mucosa (CCR9) ( 26 ). The HOXA3 transcription factor, which is expressed in early hematopoietic progenitors and subsequently down-regulated during early T cell differentiation ( 27 – 29 ), was also found highly expressed in the neonatal cells. Adding IL-12 signals to the stimulatory conditions resulted in the downregulation of this gene. Neonatal cells overexpress major neutrophil response genes, such as CEBPE and Cathepsin G (CTSG). These genes were not found significantly downregulated in this cluster, because the analysis was very stringent. However, using RT- qPCR on independent samples, we show that these genes were also downregulated by TCR/IL-12 signals (Figure 5E). For comparison, we performed the same analysis for the overexpressed genes in the naïve adult cells over those of the neonatal cells (Figure 5D). The genes downregulated by IL-12 were involved in lipid and glutamine metabolism (ALOXE3, GFPT2), ubiquitin signaling (TRIM7), and other cell functions. In Supplementary Figure 6, we present the same analysis, applying a log 2 fold change cutoff of 1, to increase the
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Natural killer cells promote early CD8 T cell responses against cytomegalovirus

Natural killer cells promote early CD8 T cell responses against cytomegalovirus

Of note, the IFN-a treatment administered to the Klra8 mice did not significantly change the level of viral replication in these animals. Very low but detectable levels of infectious viral particles were observed in both control-treated and IFN-a-injected Klra8 mice (1.9460.35 versus 1.9260.11 log pfu/spleen), which contrasted sharply with the high viral replication observed in BALB/c animals (5.260.04 log pfu/ spleen). These results demonstrate that exogenous injection of IFN-a in Klra8 mice is sufficient to decrease the numbers of cDCs and to ablate early antiviral CD8 T cell responses, and, therefore, that excessive levels of IFN-a can have a direct negative impact on antiviral immune cell responses in a manner that is independent of the level of viral replication in the host. The possibility remains that other innate cytokines, such as IL-12 and TNF-a, which are produced at much higher levels in BALB/c as compared to Klra8 mice, may also bear some contribution to this function, in a synergistic or redundant manner with IFN-a/b. In any case, our data strongly suggest that the ability of Klra8 mice to preserve an intact cDC compartment and to mount early CD8 T cell responses is in part due to their ability to control viral replication very early without the need for the host to produce high systemic levels of IFN-a/b. Altogether, our data thus identify how naturally occurring differences in the interactions between a virus and its host can tilt the balance between the various functions of IFN-a/b, and eventually other innate cytokines, towards conditions promoting the induction of early adaptive immunity, rather than the development of a state of transient immunosuppression. Early Control of Viral Load by Drug Treatment in BALB/c Mice Recapitulates the Effects of the NK Cell Activity of Klra8 Animals on DC and CD8 T Cell Responses
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en fr [The CD8+ T cell innate function in the war against cancer]. Les fonctions innées des lymphocytes T CD8 dans la lutte contre le cancer

natural killer T cells », découvertes au début des années 1990. Elles possèdent un TCR semi-invariant reconnaissant des antigènes glycolipidiques présentés par la molécule non classique du complexe majeur d’histocompatibilité (CMH) de classe I, CD1d. Depuis la découverte des iNKT, de nouveaux membres de la famille des lymphocytes T non-conven- tionnels sont régulièrement identi- fiés [1] . C’est dans ce contexte, qu’au début des années 2000, dans plusieurs modèles murins, une nouvelle population de lymphocytes T non-conventionnels a été découverte : les lymphocytes T CD8 + « inné-mémoire ». Bien que n’ayant jamais rencontré d’antigènes, ces cel- lules ont pourtant des caractéristiques de cellules mémoires qui se traduisent, notamment, par la présence d’une signa- ture fonctionnelle : la forte expression du facteur de transcription Eomeso-
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Attacking tumor cells with a dual ligand for innate immune receptors.

Attacking tumor cells with a dual ligand for innate immune receptors.

We tested this possibility by introducing lagellin into different tumor cell lines, a strategy that abrogated tumor development upon subcutaneous or intravenous injection of these lagellin-expressing cells, and induced DC- mediated tumor antigen presentation to CD4 + and CD8 +

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Transcriptional and Functional Analysis of CD1c+ Human Dendritic Cells Identifies a CD163+ Subset Priming CD8+CD103+ T Cells

Transcriptional and Functional Analysis of CD1c+ Human Dendritic Cells Identifies a CD163+ Subset Priming CD8+CD103+ T Cells

Activated DC3s Induce Priming of Naive T Cells and Differentiation of CD103 + T Cells We next aimed to understand the immunological function of DC3s and to compare it with cDC2s and monocytes. First, we decided to test the responsiveness of DC3s, cDC2s, and mono- cytes to a cocktail of Toll-like receptor (TLR) agonists. cDC2s, DC3s, and monocytes were sorted by flow cytometry from blood and stimulated overnight ex vivo. PCA analysis of the total tran- scriptome of unstimulated and stimulated populations evidenced that all subsets underwent a certain degree of convergence in their transcriptome ( Figure 6 A). In support of this, we found an important overlap in the set of activation-induced genes defined for each subset (1,344 genes; Figure 6 B). Despite the relative convergence of activated cells, we found that overnight activa- tion did not compromise cell surface discrimination of DC3s from cDC2s and monocytes ( Figure S6 A). Indeed, TLR-activated DC3s could still be discriminated from TLR-activated cDC2s by 437 DEGs or from TLR-activated monocytes by 1,293 genes ( Figure 6 C). The same was true for the pairwise comparison of activated cDC2s and circulating DC3s ( Figure S6 B). In sum, we conclude that innate activation does not trigger conversion of cDC2s or monocytes into DC3s despite induction of a common transcriptional response to TLR stimulation.
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CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

A small but consistent minority of T cells that do not express either CD4 or CD8 co-receptor provided proof-of-concept for MHC-independent modes of T cell activation (Porcelli et al., 1992). Specifically, invariant natural killer T (iNKT) cells recognize lipids presented by cluster of differentiation 1 (CD1) and mucosal associated invariant T (MAIT) cells recognize metabolites presented by MHC-related protein 1 (MR1) (Beckman et al., 1994; Kjer-Nielsen et al., 2012). On average, 15% of iNKT cells express CD4, 49% are double negative (DN), and roughly 34% express the CD8ɑɑ homodimer (O’Reilly et al., 2011). Among MAIT cells, 35% express CD8ɑɑ and 45% express CD8ɑβ (Gherardin et al., 2018). There is evidence that co-receptors are actively involved in antigen recognition by iNKT and MAIT cells. CD4 potentiates iNKT cell activation leading to sustained TCR signaling and potentiation of effector responses (Thedrez et al., 2007). Additionally, blocking CD8 with a monoclonal antibody leads to decreased MAIT cell responses to Escherichia coli (Kurioka et al., 2017). iNKT and MAIT cells can also be divided into distinct functional classes based on co-receptor expression. In humans, iNKT cells that express the CD4 co-receptor simultaneously secrete both Th1 and Th2 cytokines, and DN iNKT cells have a Th1 phenotype (Gumperz et al., 2002; Lee et al., 2002). CD8 MAIT cells express higher levels of granulysin, granzyme B, and perforin, suggesting that they are more potently cytotoxic (Dias et al., 2018). DN MAIT cells express less IFN-γ and more IL-17 than CD8 MAIT cells, and have a higher ROR-γt to T-bet ratio, indicative of a Th17 phenotype (Dias et al., 2018). Notably, these functional classes exist without two pathways for selection, antigen processing, and antigen presentation as in the case of MHC-I and MHC- II. Thus, despite early reports that suggested these “innate-like” T cells might be limited to the minority of T cells lacking expression of co-receptors, iNKT and MAIT cells are clearly part of the majority of T cells that express either CD4 or CD8.
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Two alternate strategies for innate immunity to Epstein-Barr virus: One using NK cells and the other NK cells and γδ T cells

Two alternate strategies for innate immunity to Epstein-Barr virus: One using NK cells and the other NK cells and γδ T cells

Bimodality in the human V γ9Vδ2 t cell response to EBV in vivo During acute IM, infected memory B cells accumulate in the blood and exhibit a phenotype similar to BL with type I EBV infection (Hochberg et al., 2004). We therefore investigated whether the dichotomous V γ9Vδ2 T cell response to EBV observed in vitro also occurs in vivo. We assessed frequen- cies and total cell numbers of NK cells, CD4 T cells, CD8 T cells, B cells, iNKT cells, V δ1 T cells, and Vγ9Vδ2 T cells in the peripheral blood of 17 healthy children and 17 chil- dren experiencing acute IM. Consistent with previous ob- servations (Williams et al., 2005; Hislop et al., 2007; Azzi et al., 2014), we found that the blood of children with acute IM had high numbers of NK cells (P = 0.0005) and CD8 T cells (P < 0.0001). To lesser extent, the CD4 T cell numbers were also increased in the IM patients (P = 0.04). No signif- icant changes in B cell number were observed in children with acute IM (Fig. 7 A). Overall, iNKT cell numbers were increased in children with IM (P < 0.0001), but there were no differences between patients and controls in the numbers of γδ T cells bearing Vδ1 TCR chains (Fig. 7 B). In con- trast, high numbers of V γ9Vδ2 T cells, exceeding 5% of total
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Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

In addition to changes in PD-1 + CD8 + TILs, our data show that checkpoint blockade therapy also induces changes in PD-1 − CD8 + TILs, which can contribute to the therapeutic effect. This could occur through a direct therapy-mediated effect on CD4 + regulatory T cells (Treg), as CTLA-4 is constitutively expressed on Treg and Tim-3 is highly expressed on tumor- infiltrating Tregs (Sakuishi et al., 2013). Checkpoint blockade can also act on cells of the innate immune system. Tim-3 blockade can improve the function of natural killer cells from melanoma patients (da Silva et al., 2014). Anti-Tim-3 and anti-PD-1 or PD-L1 antibodies can affect the phenotype of myeloid cells in the TME, abrogating the acquisition of an M2- like phenotype in tumor-associated macrophages (TAMs) (Jiang et al., 2016) and inducing Type 1 IFN, IL-12 and IFN- γ in CD103 + dendritic cells (DCs) in breast cancer (de Mingo Pulido et al., 2018). Similarly, PD-1 or PD-L1 blockade can promote the release of pro- inflammatory cytokines by DCs in ovarian cancer (Krempski et al., 2011; Lim et al., 2016)). These findings are in line with our observation that Type 1 IFN, IL-12, and IFN- γ signatures were induced in the effector- and memory-precursor like PD-1 − CD8 + TILs from treated mice. Thus, checkpoint blockade can act on different immune cell types within the TME to promote anti-tumor CD8 + T cell responses.
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Immune checkpoints on innate lymphoid cells

Immune checkpoints on innate lymphoid cells

functions in ILC-2s, similar to what has previously demonstrated in CD8 + T cells (Duraiswamy et al., 2011). Additional data came from exper- iments performed in mice infected with Nippostrongylus brasiliensis, a gastroin- testinal roundworm that infects rodents. ILC-2s were found to undergo mas- sive expansion in Pdc1 −/− mice upon N. brasiliensis infection, near the site of infection (mesenteric lymph nodes), to produce high levels of IL-5 and IL-13 and were also more efficient that parental ILC-2s in clearing worm burden, even without the cooperation of adaptive immune cells (Taylor et al., 2017). The same results were indeed reproduced in Rag1 −/− infected mice by using anti– PD-1 blocking antibodies, suggesting also that PD-1–targeted immunother- apy can enhance ILC-2 responses (Tay- lor et al., 2017). These data provide new clues for therapeutic intervention, not only in helminth infections for which less expensive antiparasitic drugs are currently used, but also to restore type 2 immunity in disorders that result from excessive type 1 immune responses, such as allograft rejection, contact der- matitis, or other chronic inflammatory disorders. Importantly, human ILC-2s also express PD-1. Similar to what was demonstrated in mice, human PD-1 +
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Gut Microbiota-Stimulated Innate Lymphoid Cells Support β-defensin 14 Expression in Pancreatic Endocrine Cells Preventing Autoimmune Diabetes

Gut Microbiota-Stimulated Innate Lymphoid Cells Support β-defensin 14 Expression in Pancreatic Endocrine Cells Preventing Autoimmune Diabetes

IL-22 promotes pancreatic expression of mBD14 We next sought to determine the pathway governing pancreatic expression of mBD14 and why this pathway was defective in NOD mice. In the gut, but also in other tissues including the pancreas, IL-22 has emerged as a key cytokine in tissue homeostasis partially through its ability to promote the production of AMPs (Aujla et al., 2008; Hill et al., 2013; Liang et al., 2006; Mulcahy et al., 2016; Sonnenberg et al., 2012; Wolk et al., 2004). The IL-22 receptor is highly expressed by pancreatic islets and β-cells (Shioya et al., 2008; Wolk et al., 2004), and we hypothesized that IL-22 may induce mBD14 expression in pancreatic endocrine cells. We observed that IL22 mRNA expression was reduced in pancreatic islets from female NOD mice compared with female non-autoimmune mice (Figure 4A) and male NOD mice (Figure S4A). The IL-22 level in the serum was also reduced in female NOD mice (Figure S4B). Importantly the administration of IL-22Fc to NOD mice induced the expression of mBD14 mRNA in pancreatic islets (Figure 4B). In vitro, rIL-22 induced mBD14 by targeting directly mouse and human pancreatic islets (Figure 4C, D). Moreover, rIL-22 induced the expression of mBD14 in the Min6 β-cell line (Figure S4C). As previously described (Hill et al., 2013; Kinnebrew et al., 2012), IL-22Fc also stimulated the expression of the protective AMP Reg3γ in pancreatic
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CD8[superscript +] T-cell Responses Rapidly Select for Antigen-Negative Tumor Cells in the Prostate

CD8[superscript +] T-cell Responses Rapidly Select for Antigen-Negative Tumor Cells in the Prostate

eliminated soon after T cell infiltration into the prostate, SIY-negative but Tag + cells continue to grow within the tumor bed. The presence of Tag + SIY (β-galactosidase) - tumor cells in TRP-SIY mice prior to T cell treatment further suggests that the outgrowth of Tag + SIY - tumor cells compromised the efficacy of 2C T cell treatment. This observation is likely an instance of immune-editing where immune responses keep tumors under the control but antigen-negative tumor cells eventually outgrow and escape immune surveillance. Our findings suggest that targeting multiple epitopes in poorly immunogenic tumors may increase the efficacy of immunotherapies. Indeed, in a B16-OVA model where treatment of mice with OT-1 T cells was unable to control tumor growth (6), treatment with both OT-1 and the gp-100 specific Pmel-1 T cells prevented tumor growth (21). Furthermore, our work suggests that targeting of oncogenic drivers of tumor growth with immunotherapy could be a more productive strategy. Previous attempts to use T cells that recognize Tag epitopes in the TRAMP model have provided mixed results with regards to reduction in tumor burden (11, 12). Nevertheless, other models have demonstrated the therapeutic benefit of focusing the immune response toward overexpressed oncogenes, including Tag (18). The efficacy of combination immunotherapies that target oncogene epitopes and non-oncogene epitopes should be investigated in this and other models.
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Tissue Infiltrating LTi—Like Group 3 Innate Lymphoid Cells and T Follicular Helper Cells in Graves' and Hashimoto's Thyroiditis

Tissue Infiltrating LTi—Like Group 3 Innate Lymphoid Cells and T Follicular Helper Cells in Graves' and Hashimoto's Thyroiditis

Importantly, we demonstrated a significant positive correlation between Tfh and LTi-like ILC3 cells. This is a key finding as both populations are involved in the development of tertiary lymphoid organs and of GCs ( 21 ). These GCs are involved in the production of local autoantibodies in AITDs. Moreover, the binding of TPO and Tg within the thyroid TLS of AITDs patients favors the local presence/production of anti-TPO and anti-Tg autoantibodies ( 12 ). Indeed, whilst GCs were present in the thyroids of all HT patients and almost all GD Group 1 patients, they were absent in most of GD Group 2 patients. Morevover, we also observed in a limited number of analyzed samples infiltrating antibodies producing B cells in HT and GD group 1 tissues while those were absent in control and Group 2 GD tissues. Even if no correlation was observed between TRAb levels and the percentage of CXCR5 + PD-1 hi CD4 + cells or the presence of GCs, we observed that GD Group 2 patients who did not develop local thyroid TLS and GCs were more likely to develop ophthalmopathy than GD Group 1 patients. Based on this and because the evolution of ophthalmopathy is often independent of the evolution of the thyroid disease ( 33 , 34 ), we hypothesize that:
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Immunomodulatory properties of human MuStem cells: assessing their impact on adaptive and innate immunity

Immunomodulatory properties of human MuStem cells: assessing their impact on adaptive and innate immunity

1: Angionetcs Inc. 2: New York University, School of Medicine Generx (Ad5FGF-4) is currently in Phase 3 clinical trial as a therapeutic angiogenesis product candidate for the treatment of patients with refractory angina. Experiments were performed in cultured cells to explore whether FGF-4 is capable to interact with the adenoviral vector and endogenous VEGF. The poten- tial interaction with the Ad5 vector was tested in cultured RCS chondrocytes and 3T3 fibroblasts. Ad5GFP (M.O.I. 10vp/cell) was added to the cells, which were treated 24 hours later by FGF-4 (10ng/ml). FGF-4 stimulated gene expression 5-10 fold (GFP fluorescence and Western blot) in both RCS (growth in- hibition) and 3T3 cells (growth promotion). This novel obser- vation suggests a positive interaction between the Ad5 vector and the transgene of Generx, potentially leading to increased extent and duration of gene expression after Ad5FGF-4 ad- ministration. The interaction between FGF-4 and endogenous VEGF was studied in a co-culture system of human dermal fibroblasts (HDF) and human umbilical vein endothelial cells (HUVEC). FGF-4 (1-8 ng/ml) stimulated new vascular network formation, including tube elongation and branching, which was significantly inhibited by both anti-VEGF (4 ug/ml) and anti- VEGFR2 (30 ug/ml) antibodies. FGF-4 stimulated the release of VEGF from HDF, but not from HUVEC. These results dem- onstrate that FGF-4 stimulates the release of VEGF from non- endothelial cells and FGF-4 and VEGF act synergistically on endothelial cells in the formation of new vascular structures. OR011
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Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

<0.001 Fig. 6 Epigenetic transcriptional repression in exhausted HCV speci fic CD8+ T cells from chronic patients. a Six distinct functional groups of pathways enriched in upregulated genes (red) in T1/early and displaying the opposite trend (blue) in T2/late identi fied by GSEA (MSigDB, C2 canonical pathways and C5 Gene Ontology sets) in HCV-speci fic CD8+ T cells from chronically evolving patients. NES = normalized enrichment score; FDR = False Discovery Rate. In red, above the p-value columns, is shown the total number of genes significantly upregulated in T1/early and downregulated in T2/late in each group of pathways. b Heat-maps comparing the expression pro files of leading genes belonging to the DNA repair/damage response, metabolism and cell signaling pathways in chronic and resolved infections (see also the T2 sheets in Supplementary Data 2). c Mitochondrial (left panel, JC-1 staining) and proteasomal (right panel, ProteoStat staining) functions were assessed in dextramer-stained HCV-speci fic CD8+ T cells from T2/late chronic and T2/late self-limited HCV infection and in healthy controls following PBMC overnight stimulation with anti-CD3/CD28. MFI, Median Fluorescence Intensity. d Heat- map comparing the expression levels (average log 2 fold change) of epigenetic regulatory complexes (derived from the EpiFactors database as detailed in
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