The mode of recognition of tumor antigens by noncytolytic-type antitumor T cells: Role of antigen-presenting cells and their surface class I and class II H-2 molecules

1988 ◽  
Vol 27 (3) ◽  
Author(s):  
Kohichi Sakamoto ◽  
Hiroto Nakajima ◽  
Jun Shimizu ◽  
Tatsuo Katagiri ◽  
Chiharu Kiyotaki ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Antigens ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Class I ◽  
Antigen Presenting

A Crucial Role for Antigen Presenting Cells in Donor CD4+CD25+ Regulatory T Cell Mediated Suppression of Experimental Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 688-688
Author(s):  
Isao Tawara ◽  
Tomomi Toubai ◽  
Chelsea Malter ◽  
Yaping Sun ◽  
Evelyn Nieves ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Indoleamine 2 ◽  
Effector Phase ◽  
Antigen Presenting

Abstract Abstract 688 Several lines of evidence show that donor derived mature CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress experimental GVHD. The mechanism of GVHD suppression by donor Tregs is, however, not well understood. Recent observations have brought in a renewed focus on the role of professional antigen presenting cells (APCs) in the induction and maintenance of GVHD by alloreactive T cell effectors (Teffs). But the role of APCs in modulating the responses of Tregs after allogeneic BMT is not known. We first tested the requirement of host APCs in Treg mediated regulation of GVHD. We utilized a clinically relevant CD8+ T cell dependent MHC matched but miHA disparate C3H.SW (H-2b) → wild type (wt) or Class II deficient Abb (II-/-) B6 (H-2b) model of GVHD because host APCs and target tissues from the Abb animals do not express class II and as such donor CD4+CD25+ Tregs will not directly interact with the host tissues while alloreactive CD8+ T cells could still respond to miHA allo-antigens presented by the intact class I on host APCs. The recipient Abb (II-/-) and wt B6 animals were lethally irradiated and transplanted with 2 × 105 CD8+ T cells along with or without CD4+CD25+ Tregs at 1:2 ratio from either syngeneic B6 or allogeneic C3H.SW animals. The wt recipients that received Tregs showed significantly better survival compared with the wt animals that did not receive any Tregs (P< 0.01) while the class II-/- animals showed similar GVHD mortality regardless of Treg infusion (P>0.8). To confirm whether the lack of Treg mediated protection was only due to the absence of interaction with host type APCs and also to exclude the possibility of development of Tregs from the infused BM we thymectomized wt B6 animals and then generated [B6 B6] controls and the [Abb B6] chimeras. These chimeric animals were used as recipients in a second BMT and transplanted with CD8+ Teffs and Tregs from allogeneic C3H.SW mice. Tregs reduced GVHD mortality in the [B6 B6] (P<0.01) but not in the [Abb B6] animals (P>0.7). We next evaluated whether host APC expression of allo-antigens alone was sufficient for Treg mediated GVHD protection in the absence of class II expression on target tissues by generating [B6 B6] and [B6 Abb] chimeras and found that Tregs demonstrated equivalent GVHD protection even when the class II allo-antigens were expressed only on the host APCs. Mechanistic studies demonstrated that Tregs significantly inhibited the expansion of CD8+ Teffs on days +10 and 17 after BMT in the spleens of the WT recipients (P<0.05) but not in the class II-/- animals. However, infused Tregs demonstrated reduced expansion in the class II-/- animals only early after BMT (on day +10) but was equivalent at later time-point (days 17 and 29) to the WT recipients. We further determined the mechanisms by which host APCs might contribute to Treg mediated protection. To this end we used IL-10-/-, indoleamine 2, 3 dioxygenase (IDO)-/- deficient animals and generated [IL-10-/- B6] and [IDO-/- B6] animals as recipients. Tregs mitigated GVHD mortality regardless of the ability of the host APCs to express IL-10 or IDO. We next determined whether Tregs suppressed Teffs in their activation phase at the level of their interaction with host APCs or in the effector phase. C3H.SW CD8+ T cells were primed (both in vivo and ex vivo with B6 allo-antigens) and then infused into the [β2mg-/- B6] animals such that pre-activated CD8 Teffs would still be able to initiate GVHD without the need for host APCs for their activation. Infusion of donor Tregs into [β2mg-/- B6] animals that were transplanted with the pre-activated Teffs mitigated GVHD severity demonstrating that Tregs, once activated by host APCs, were capable of suppressing Teff cells in their effector phase. Collectively our data show (a) host APCs are critical (b) expression of allo-antigens on host target tissues is not obligatory (c) host derived IL-10 and IDO are not critical for Treg mediated GVHD protection and (d) Tregs can mitigate GVHD by suppressing alloreactive Teffs in the effector phase even after they have been activated. Disclosures: No relevant conflicts of interest to declare.

Engineered Antigen- Presenting Cells Expressing Human HLA Class-II DR Alleles Support Efficient Enrichment and Expansion of Antigen Specific Th1 CD4[+] T-Cells Which Are Functionally Augmented by IL-15Rα/IL-15 Complexes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1905-1905
Author(s):  
Aisha N. Hasan ◽  
Rosanna J. Ricafort ◽  
Annamalai Selvakumar ◽  
Ekaterina Doubrovina ◽  
Isabelle Riviere ◽  
...  
Keyword(s):  
T Cells ◽  
Peptide Pool ◽  
Antigen Presenting Cells ◽  
Hla Class I ◽  
Class Ii ◽  
Hla Class Ii ◽  
Class I ◽  
Invariant Chain ◽  
Antigen Presenting ◽  
Nih 3T3

Abstract Abstract 1905 Previous studies have affirmed the therapeutic efficacy of adoptively transferred antigen specific CD8+ and CD4+ T-cells (TC) against viral infections and tumors. A major challenge in optimizing this approach is to develop strategies to permit generation of CD4+ and long lived CD8+ TC of defined antigen specificity. We previously described a panel of NIH 3T3 based artifical antigen presenting cells (AAPC) for the immediate generation of HLA class-I restricted CMVpp65 specific CD8+ TC. We now describe a panel of NIH 3T3 based AAPC, each transduced to express a shared HLA DRA 0101 alpha chain and one of the following β chains of the human HLA class-II alleles DRB1 0301, 0701, 1501, 0401 and 1101. At least one of these alleles is inherited by 61% and 59% of caucasians and blacks respectively. These AAPCs were also transduced to co-express the human TC costimulatory molecules B7.1, ICAM-1 and LFA-3. Sensitization of TC from seropositive donors in the presence of IL-2 with AAPCs sharing one of these alleles, either loaded with a CMVpp65 peptide pool or transduced to express the CMV pp65 protein, resulted in 33–71 fold expansion of CMVpp65 specific CD4+ TC that exhibited a Th1 cytokine profile, producing TNF-α and IFNγ in response to the same CMVpp65 epitopes. These TC were also cytotoxic against peptide loaded HLA class-II sharing targets. Epitope mapping demonstrated that the HLA DRB1 0301 restricted TC responded to a CMVpp65 epitope known to be presented by this allele QEFFWDANDIY (aa 509–527) and to an unreported epitope DVEEDLTMTRN (aa 245–263). The DRB1 0701 restricted CD4+ TC responded to 4 different epitopes. Two of these also included nonamer peptide sequences previously reported to be presented by HLA class-I alleles; Q IFLEV QAIRE and PQYSEH PTFTS presented by HLA B44, and a third AGILARNLVPM, contained an epitope presented by HLA B0801. The fourth epitope, KYQEFFWDANDIY is known to be also presented by HLA DRB1 0301. The DRB1 1501 restricted CD4+ TC were also responsive to a known class-II epitope LLQTGIHVRVS (aa 37–55) as well as a new epitope LVSQYTPDSTP (aa 53–71). CD4+ TC from 3 donors also responded to CMVpp65 when sensitized with autologous DCs loaded with CMVpp65 peptide pool, and each recognized the same epitopes as TC sensitized with the class-II AAPCs. Supplementation of TC cultures with soluble IL-15Rα/ IL-15 complexes markedly augmented the proportion of IFNg+ CD4+ TC, while increasing concentrations of IL-2 resulted in generation of Th2 type CD4+ TC generating IL-4, IL-5 and IL-2 in response to re-stimulation with CMVpp65 peptides. This system can therefore be harnessed by cytokine modulation to selectively generate CD4+ TC with a Th1, or Th2 cytokine profile. The fact that the class-II AAPC transduced to express the full sequence of CMVpp65 are able to process and present antigenic epitopes on the surface of the expressed HLA class-II allele in the absence of the human invariant chain and HLA-DM suggests that the mouse 3T3 cells contain sufficiently homologous proteins to permit the transfer of processed peptides to human Class-II alleles for presentation. Alternatively, invariant chain independent pathways could permit delivery of certain immunogenic epitopes to the expressed class II HLA alleles. The repertoire of epitopes presented by the Class-II AAPCs with or without the invariant chain is currently under study. Our results suggest that the panel of AAPCs expressing these HLA DRB1 alleles provides a novel and rapid approach for the generation of Th1 CD4+ virus-specific TC of desired HLA class-II restriction for adoptive therapy of CMV disease to foster lasting immunity with co-infused CMVpp65-specific CD8+ TC. Class-II AAPCs used with different concentrations or types of cytokines may also be useful to generate other functional subsets of CD4+ TC to promote tolerance or enhance tumor- specific immunity. Disclosures: No relevant conflicts of interest to declare.

Abstract 252: Interleukin-27 Signaling Regulates Myeloid Cells Activation in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Iuliia Peshkova ◽  
Aliia Fatkhullina ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Antigen Presenting Cells ◽  
Atherosclerotic Lesions ◽  
Mediators Of Inflammation ◽  
Antigen Presenting ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Atherosclerosis is a lipid-driven inflammatory disease characterized by the progressive plaque growth in the vessels. Cytokines are important mediators of inflammation and atherosclerosis. While pro-inflammatory cytokines were extensively investigated, little is known about the role of anti-inflammatory cytokines as to their ability to control vascular inflammation. We tested whether immunoregulatory IL-27R signaling is important to control inflammation in mouse models of atherosclerosis. We found that atherosclerosis-prone mice with hematopoietic deficiency of IL-27R ( Ldlr -/- mice reconstituted with bone marrow from Il27ra -/- ) or global deficiency ( Il27ra -/- x Apoe -/- ) developed significantly larger atherosclerotic lesions compared to controls. Atherosclerotic lesions in IL-27R deficient mice contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in atherosclerotic aortas. Using two-photon microscopy, we found enhanced interactions between antigen presenting cells and T cells in the aortas of IL-27R deficient mice accompanied by enhanced CD4 T cell proliferation. Moreover, macrophages in Il27ra -/- aortas also demonstrated enhanced ability to produce pro-inflammatory cytokines, including IL-1. The blockade of IL-1R signaling, however, strongly suppressed atherosclerosis progression in IL-27R deficient but not control mice, suggesting an important role of IL-27 in the regulation of IL-1 production in atherosclerosis. Overall, our data demonstrate that IL-27R signaling in atherosclerosis is required to control function of antigen presenting cells modulating subsequent T cell activation in the aortas. Moreover, it controls macrophage activation and pro-inflammatory myeloid cell-derived cytokine production. These mechanisms altogether curb pathogenic T cell lineage differentiation and, thus, atherosclerosis, suggesting potent anti-atherogenic role of IL-27.

scholarly journals Selective tumor antigen vaccine delivery to human CD169+antigen-presenting cells using ganglioside-liposomes

2020 ◽  
Vol 117 (44) ◽  
pp. 27528-27539
Author(s):  
Alsya J. Affandi ◽  
Joanna Grabowska ◽  
Katarzyna Olesek ◽  
Miguel Lopez Venegas ◽  
Arnaud Barbaria ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Dependent Manner ◽  
Cross Presentation ◽  
Vaccine Carrier ◽  
Antigen Presenting

Priming of CD8+T cells by dendritic cells (DCs) is crucial for the generation of effective antitumor immune responses. Here, we describe a liposomal vaccine carrier that delivers tumor antigens to human CD169/Siglec-1+antigen-presenting cells using gangliosides as targeting ligands. Ganglioside-liposomes specifically bound to CD169 and were internalized by in vitro-generated monocyte-derived DCs (moDCs) and macrophages and by ex vivo-isolated splenic macrophages in a CD169-dependent manner. In blood, high-dimensional reduction analysis revealed that ganglioside-liposomes specifically targeted CD14+CD169+monocytes and Axl+CD169+DCs. Liposomal codelivery of tumor antigen and Toll-like receptor ligand to CD169+moDCs and Axl+CD169+DCs led to cytokine production and robust cross-presentation and activation of tumor antigen-specific CD8+T cells. Finally, Axl+CD169+DCs were present in cancer patients and efficiently captured ganglioside-liposomes. Our findings demonstrate a nanovaccine platform targeting CD169+DCs to drive antitumor T cell responses.

scholarly journals Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 202-210 ◽  
Author(s):  
ML Disis ◽  
H Bernhard ◽  
FM Shiota ◽  
SL Hand ◽  
JR Gralow ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Delayed Type Hypersensitivity ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Antigen Presenting ◽  
Stimulating Factor

Abstract The current studies evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. An important issue for developing vaccine therapy for human malignancy is identifying adjuvants that can elicit T-cell responses to proteins and peptides derived from “self” tumor antigens. GM-CSF, in vitro, stimulates the growth of antigen-presenting cells such as dendritic cells and macrophages. Initial experiments examined whether GM-CSF injected into the skin of rats could affect the number or character of antigen presenting cells, measured as class II major histocompatability complex expressing cells, in lymph nodes draining the injection site. Intradermal (id) inoculation of GM-CSF every 24 hours for a total of five inoculations resulted in an increase of class II+ fluorescing cells that peaked at the fourth inoculation. Subcutaneous (sq) inoculation resulted in an increase of class II+ fluorescing cells that peaked following the second inoculation, then decreased over time. Using this schema for “conditioning” the inoculation site, GM-CSF was administered id or sq for five injections and a foreign antigen, tetanus toxoid (tt), was given at the beginning or the end of the immunization cycle. Id immunization was more effective than sq at eliciting tt specific immunity. In addition, GM-CSF id, administered as a single dose with antigen, compared favorably with complete Freund's adjuvant (CFA) and alum in eliciting tt specific antibody and cellular immunity. We have shown that immunity to rat neu (c-erbB-2) protein, an oncogenic self protein, can be generated in rats by immunization with peptides derived from the normal rat neu sequence plus CFA. The current study demonstrates that rat neu peptides inoculated with GM-CSF could elicit a strong delayed type hypersensitivity reaction (DTH) response, whereas peptides alone were non-immunogenic. GM-CSF was as effective as CFA in generating rat neu specific DTH responses after immunization with a neu peptide based vaccine. Soluble GM-CSF is a potent adjuvant for the generation of immune responses to foreign proteins as well as peptides derived from a self tumor antigen.

Abstract 44: Interleukin-27 Signaling is a Critical Regulator of Inflammation in Atherosclerosis

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ekaterina Koltsova ◽  
Gisen Kim ◽  
Sibylle von Vietinghoff ◽  
Mitchell Kronenberg ◽  
Klaus Ley
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Inflammatory Cytokines ◽  
Arterial Wall ◽  
Antigen Presenting Cells ◽  
Cytokine Signaling ◽  
Interleukin 27 ◽  
Anti Inflammatory ◽  
Antigen Presenting

Atherosclerosis is chronic inflammatory disease, which affects blood vessels. While the pro-atherogenic role of various inflammatory cytokines was broadly investigated, less is known about contribution of anti-inflammatory cytokines with regard to their ability to control inflammation in vivo. Interleukin 27 (IL-27) was shown to play immunosuppressive function via multiple mechanisms. We tested whether IL-27 signaling is important to restrain inflammation in mouse models of atherosclerosis. We transplanted bone marrow from Il27ra -/- or Il27ra +/+ mice into atherosclerosis prone Ldlr -/- littermates. Recipients of Il27ra -/- marrow showed significantly larger atherosclerotic lesions in aortic roots, aortic arches and, most strikingly, in the abdominal aorta. Aortas contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. Concomitantly, the levels of IL-17A and IL-6 were significantly elevated in aortic tissue. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in aortas, atherosclerotic plaque growth and disease progression. Moreover, using our recently developed live imaging by two-photon microscopy, we found enhanced interaction between antigen presenting cells and T cells in the arterial wall of Il27ra deficient mice. Overall, IL-27 signaling in bone marrow-derived cells regulates atherosclerosis by controlling interaction of antigen presenting cells and T cells in the arterial wall and therefore curbing Th17 and Th1 lineage differentiation, TNF and IL-17 dependent chemokine expression and subsequent myeloid cell accumulation. Thus, our work establishes the importance of anti-inflammatory cytokine signaling in atherosclerosis and demonstrates novel anti-atherogenic role of IL-27.

Nitrosylation of Platelet MHC Class I Molecules Directs Their Movement into the Immunosuppressive MHC Class I Processing Pathway within Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 837-837
Author(s):  
John W. Semple ◽  
Edwin R. Speck ◽  
John Freedman
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Brefeldin A ◽  
Antigen Presenting Cells ◽  
Class I ◽  
Antigen Presenting ◽  
Platelet Transfusions

Abstract Previous studies have demonstrated that recipient mice require the production of nitric oxide (NO) within their antigen presenting cells (APC) in order to generate IgG anti-donor immunity against allogeneic platelet transfusions. NO has a complex biochemistry and several of its conjurors could be involved in this response; the most obvious is peroxynitrite (ONOO-) generated by the spontaneous combination of NO and superoxide (O2•−). ONOO- is a potent oxidant that can spontaneously nitrosylate lysine and tyrosine residues in proteins within the phagolysosome. To address the role of ONOO- in platelet immunity, we transfused GP91 PHOX knockout mice that lack the ability to produce O2•− and thus ONOO-. Results show that when wild type C57BL/6 mice were transfused with allogeneic BALB/c platelets, they developed a weak IgG anti-donor antibody response by the fifth transfusion. In contrast, PHOX KO mice generated IgG anti-donor antibodies by the 2nd transfusion and their IgG anti-donor antibody titres were significantly higher than the WT recipients. This suggested that ONOO- and protein nitrosylation may be linked with an immunosuppressive event within the recipient. This was confirmed by demonstrating that in vitro nitrosylation of platelet antigens with the ONOO- donor SIN-1 inhibited the ability of the platelets to mount an IgG immune response when transfused into allogeneic recipients. Nitrosylated platelet antigen trafficking within recipient APC was assessed by using adherent macrophages and various inhibitors of processing. When adherent APC were pulsed with nitrosylated platelet antigens in the presence of either Brefeldin A or proteosome inhibitors, IgG anti-platelet immunity against the platelets was restored. Furthermore, the IgG immunity could also be rescued against the nitrsosylated platelets if the recipients were first depleted of CD8+ T cells by injection of a monoclonal antibody. These results suggest that if platelet antigens are nitrosylated within antigen presenting cells, they are preferentially shunted to the MHC class I processing pathway and presented to CD8+ T cells that suppress the IgG immune response. Thus, it appears that reactive oxygen species act as intracellular regulators that determine whether a productive IgG immune response against platelet transfusions will occur.

Sign in / Sign up

Export Citation Format

Share Document