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Dendritic Cells Control the Balance between Tolerance and Autoimmunity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Simon W. F. Milling, G. Gordon MacPherson
Some of the best-described subsets of DCs have been identified in the mouse spleen. This contains three distinct populations of interstitial DCs, all of which express MHC class II and CD11c molecules at high levels and are capable of stimulating naive lymphocytes in a mixed leukocyte culture system.2 These three populations can be discriminated based on their expression of surface markers commonly used to differentiate between T cells, CD4 and CD8. Unlike T cells, however, the DCs express the CD8 molecule as a homodimer of two CD8a chains, while CD8+ T cells express a CD8αβ heterodimer. The DCs are CD4-CD8α- (“double negative” or DN), CD4+CD8α-, or CD4-CD8α+. All these subtypes in spleen have a rapid turnover, with a half-life in spleen of 1.5 to 2.9 days, all develop from bone marrow precursors, and none of the subtypes is the precursor of another. CD8α+ DCs are found in the T-cell-rich areas of the spleen, lymph nodes and Peyer’s patches. By contrast, CD8α- DCs are localized in the marginal zones of the spleen, the sub-capsular sinuses of the lymph nodes, and the sub-epithelial dome of the Peyer’s patches. These CD8α- DCs can, however, rapidly migrate to the T cell areas after stimulus by microbial products including lipopolysaccharide3 (LPS) or extracts from toxoplasma.4
Mucosal vaccine strategies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Nils Lycke, Jan Holmgren, Harry B. Greenberg
The bacterial enterotoxins or derivatives thereof, typified by CT and E. coli heat-labile enterotoxin, are AB5 complexes and carry an A1 subunit that is an ADP-ribosylating enzyme and five B subunits that bind distinct ganglioside receptors present on most nucleated mammalian cells. Because gangliosides reside in the cell membrane of all nucleated cells, the binding is promiscuous; hence, the enzyme can affect virtually all cells in the human body. Following binding to the receptor, the holotoxins ADP-ribosylate the Gsα membrane protein and stimulate adenylate cyclase, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). This property makes them highly toxic but also contributes to their excellent adjuvant function in vivo. Thus, simply admixing or coupling of antigens to CT and repeated oral immunizations are highly effective ways to generate mucosal immune responses to soluble antigens and haptens (Figure 30.4). The B subunits of CT and heat-labile enterotoxin are responsible for binding to the ganglioside receptors on the cell membrane. Following mucosal administration, CT and heat-labile enterotoxin have been reported to host variable effects on priming of TH1, TH2, TH17, and Treg cells. Whereas CT has mostly been associated with TH2 responses in the past and somewhat weaker TH1 immunity, heat-labile enterotoxin has been found to have a more balanced effect on priming of TH1 and TH2 types of immunity. However, with a growing knowledge about the immunobiology of TH17 cells, it has been found that both holotoxins are excellent inducers of these cells. Nonetheless, recent investigations identify classical DCs to be the adjuvant targets for CT and have found that priming into TH1, TH2, and TH17 as well as follicular helper T cells (TFH) are all well enhanced by CT adjuvant. Whereas CT has been found to depend on IL-17 for some adjuvant functions, this has been linked to an effective TH17 priming ability, but it is still unclear to what extent its adjuvant effects are directly associated with TH17 cell functions. Rather, its immunomodulating effects on the DCs in various tissues would be expected to be the mechanism of action, and the antigen- and tissue-specific factors influence impacts on the adjuvant outcome. Furthermore, a few studies have pointed out that Treg cells may be enhanced by CT adjuvant, but this needs to be further investigated. In fact, it is more likely that CT reduces Treg-development and favors Tfh differentiation and this could be the key role of CT acting on DCs in the PP. Finally, other studies have indicated that CD8+ T cells are selectively lost following CT administration, as are CD8α+ DCs. Taken together, it is still poorly understood what the adjuvant mechanism of these holotoxins is at the molecular level, and in particular, whether their adjuvant function is dependent on cAMP induction, while it has recently been demonstrated that ADP-ribosylation of Gsα in DCs is critically required for the adjuvant effect.
An adjuvant-containing cDC1-targeted recombinant fusion vaccine conveys strong protection against murine melanoma growth and metastasis
Published in OncoImmunology, 2022
Mohammad Arabpour, Sanchari Paul, Hanna Grauers Wiktorin, Mustafa Kaya, Roberta Kiffin, Nils Lycke, Kristoffer Hellstrand, Anna Martner
Single-cell suspensions from lungs were incubated with live dead aqua for 40 minutes at 4°C and then stained with CD8- or a CD4-based panel of antibodies. For the CD8 panel, cells were stained with anti-CD3 BUV737 (clone 17A2, BD Horizon) and anti-CD8a APC (clone 53–6.7, BD Biosciences) antibodies, washed and then stained with MHCI-SIINFEKL tetramer-PE (Proimmune). For the CD4-based panel, cells were surface-stained with anti-CD3 BUV737 (Clone 17A2) and anti-CD4 AF700 (clone RM4-5, BD Pharmingen) antibodies, followed by fixation and permeabilization (Thermofisher Scientific) and intracellular staining with an intracellular panel of antibodies comprising anti-Tbet BV786 (clone 04–46, BD Horizon), anti-Gata3 PE (clone TWAJ, Invitrogen), anti-RORγt PE (clone Q31-378, BD Horizon), and anti-Foxp3 AF647 (clone150D, Biolegend). For analysis of CD4 and CD8 memory phenotypes, cells were stained with anti-CD3 BUV737, anti-CD4 AF700, anti-CD8a APC, anti-CD103 BV421 (2E7), anti-CD69 APCCy7 (H1.2F3), anti-CD44 FITC (IM7), and anti-CD62L BV605 (MEL-14) antibodies. Cells were acquired on a BD LSR Fortessa and analyzed using FlowJo v10.
OX40 and 4-1BB delineate distinct immune profiles in sarcoma
Published in OncoImmunology, 2022
MJ Melake, HG Smith, D Mansfield, E Davies, MT Dillon, AC Wilkins, EC Patin, M Pedersen, R Buus, AA Melcher, K Thway, AB Miah, SH Zaidi, AJ Hayes, TR Fenton, KJ Harrington, M McLaughlin
We looked at CD8A, CD20, CD4, and CD68 in TCGA data for UPS split by 4–1BB status (Figure 2(b)). The highest transcript levels of CD20 and CD4 were observed in the 4–1BB-high group, both showing statistical significance. On an individual sample basis, patients with the highest transcript levels for CD8A fell within both the high and intermediate groups, but no significance was observed between groups. The trend for CD68 was less clear. Looking at transcripts linked to activation, there was a significant difference in GZMB and CD69 (Figure 2(c)). Significant increases were observed in the 4–1BB-high group versus 4–1BB-low for both the Treg marker FOXP3, and the T-cell exhaustion marker TOX (Figure 2(d)). This corresponded to the highest levels of co-inhibitory receptor transcripts (PDCD1/PD-1, CD274/PD-L1, CTLA4, HAVCR2/TIM3, and TIGIT) occurring in the 4–1BB-high group (Figure 2(e)).
Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma
Published in OncoImmunology, 2021
Xin-Wen Zhang, Katrin Huck, Kristine Jähne, Frederik Cichon, Jana K. Sonner, Friederike Ufer, Simone Bauer, Marcel Seungsu Woo, Ed Green, Kevin Lu, Michael Kilian, Manuel A. Friese, Michael Platten, Katharina Sahm
In the tumor microenvironment, resident Batf3-dependent cDC1s initiate effective T cell recruitment by secretion of T cell recruiting chemokines CXCL9/CXCL10,47 which directed us to further investigate the antigen-specific T cell response following DC vaccination with Arc/Arg3.1-expressing BMDCs. Indeed, T cell trafficking to the TME was dependent on Arc/Arg3.1 expression in injected DCs (Fig. 3B, C). Moreover, an increased frequency of adoptively transferred gp100-specific T cells was associated with an increase in donor derived gp100-loaded DCs in the tumor and tdLN exclusively after injecting Arc/Arg3.1-overexpressing DCs (Fig. 6A, B). The expression of T cell recruiting chemokines by Arc/Arg3.1-expressing migratory DCs (Fig. S1D) supports the hypothesis that Arc/Arg3.1-expressing DCs in the TME are involved in the recruitment of antigen-specific T cells. In the lymphoid organs, resident CD8a+ cDC1s are essential for cross-presentation of tumor-derived antigens to T cells leading to T cell proliferation and activation.48,49 Also, cross presentation by a distinct Batf3-dependent DC subpopulation within the tumor microenvironment itself mediated T cell activation and determined tumor rejection.25 It remains to be elucidated, whether processing of tumor antigens by injected donor-derived DCs for cross presentation to CD8+ cytotoxic T cells might be a reason for the observed decrease of MHC class II expression on donor-derived gp100-loaded DCs in the tumor (Fig. 2D).50