scholarly journals Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells

2019 ◽  
Author(s):  
Marta E Polak ◽  
Sofia Sirvent ◽  
Kalum Clayton ◽  
James Davies ◽  
Andres F. Vallejo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Transcription Factor ◽  
Antigen Presentation ◽  
Langerhans Cells ◽  
Mhc I ◽  
Cross Presentation ◽  
Mhc Ii ◽  
T Cell Immune Responses ◽  
Dependent Protein ◽  
Chromatin Profiling

AbstractLangerhans cells (LCs) in the epidermis present MHC I and MHC II-restricted antigens thereby priming either CD8 or CD4 T cell immune responses. The genomic programs and transcription factors regulating antigen presentation in LCs remain to be elucidated. We show human LCs are highly efficient in MHC I-antigen cross-presentation but lack the transcription factor IRF8 that is critical in dendritic cells. LC migration from the epidermis enhances their ability to cross-present antigens and is accompanied by the induction of the transcription factor IRF4, whose expression is correlated by scRNA-seq with genes involved in ubiquitin-dependent protein degradation. Chromatin profiling reveals enrichment of EICE and AICE composite DNA binding motifs in regulatory regions of antigen-presentation genes, which can be recognized by IRF4 in conjunction with PU.1 or BATF3 expressed in LCs. Thus, the genomic programming of human LCs including inducible expression of IRF4 with enhanced cross-presentation distinguishes them from conventional dendritic cells.

scholarly journals High Levels of a Major Histocompatibility Complex II–Self Peptide Complex on Dendritic Cells from the T Cell Areas of Lymph Nodes

1997 ◽  
Vol 186 (5) ◽  
pp. 665-672 ◽  
Author(s):  
Kayo Inaba ◽  
Maggie Pack ◽  
Muneo Inaba ◽  
Hiraki Sakuta ◽  
Frank Isdell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mhc I ◽  
Peptide Complex ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Peripheral Lymph ◽  
Free Media ◽  
Very High

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47–58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-Ab and a peptide derived from I-Eα, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II–peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.

scholarly journals P04.06 mucosal immunization with a cDC1-targeted CTA1 adjuvant vaccine confers protection against melanoma metastasis

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A39.1-A39
Author(s):  
M Arabpour ◽  
S Paul ◽  
R Kiffin ◽  
HG Wiktorin ◽  
K Hellstrand ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Pulmonary Metastases ◽  
T Cell Immunity ◽  
Metastasis Formation ◽  
Mhc I ◽  
Mhc Ii ◽  
Cell Immunity

BackgroundSpecific targeting of anti-cancer vaccines to dendritic cells (DCs) has been shown to mount efficient immune responses against tumor cells. Classical CD103+dendritic cells (also called cDC1) have an inherent ability to cross-present antigens to CD8+ cytotoxic T cells. Here we have explored an anti-tumor vaccine that specifically targets cDC1 cells for protection against and elimination of metastatic melanoma. The vaccine contains the cholera toxin A1 subunit (CTA1) adjuvant and is targeted to cDC1 cells through an anti-CD103 single chain antibody (CD103 scFv).Material and MethodsC57BL/6 mice were injected with wild type or ovalbumin (OVA) expressing B16 melanoma cells either subcutaneously (s.c.) to establish solid tumors, or intravenously (i.v.) to allow the formation of pulmonary metastases. Before or after establishment of tumors, mice were intra-nasally inoculated with a vaccine composed of a CD103 scFv element fused to the adjuvant CTA1 and the MHC I H2kd-restricted OVA epitope SIINFEKL together with the MHC II H2kd-restricted OVA epitope p323 or just the p323 peptide alone (i.e. CTA1-SIINFEKL-p323-CD103 and CTA1-p323-CD103, respectively). Control mice were inoculated with PBS. The growth of solid tumors was carefully monitored and the development of pulmonary metastases was determined 2–3 weeks after tumor cell injection. In addition, antigen-specific T cell immunity following intranasal immunization was evaluated.ResultsTargeting MHC I and MHC II tumor cell epitopes to cDC1, via CD103 ScFv, in conjunction with the CTA1 adjuvant elicited strong tumor specific and protective CD8+ T cell responses as well as CD4+ T cell immunity. Immunization with the CTA1-SIINFEKL-p323-CD103 vaccine significantly reduced the growth of established solid B16F1-OVA melanomas (P<0.001) and potently prevented metastasis formation (P<0.01). Control immunizations with the CTA1-p323-CD103 vaccine tended to reduce metastasis, but tumor-specific CD8+ T cells were required for full therapeutic protection.ConclusionTargeting tumor specific CD8+ T cell epitopes to cDC1, in the context of a powerful adjuvant such as CTA1, leads to the development of efficient anti-tumor immune responses. Our results point towards the utility of cDC1-targeted vaccines in the treatment of established tumors or as a means to prevent metastasis formation.Disclosure InformationM. Arabpour: None. S. Paul: None. R. Kiffin: None. H.G. Wiktorin: None. K. Hellstrand: None. N. Lycke: None. A. Martner: None.

scholarly journals MARCH1-mediated ubiquitination of MHC II impacts the MHC I antigen presentation pathway

PLoS ONE ◽  
2018 ◽  
Vol 13 (7) ◽  
pp. e0200540 ◽  
Author(s):  
Kayla R. Wilson ◽  
Haiyin Liu ◽  
Geraldine Healey ◽  
Vivian Vuong ◽  
Satoshi Ishido ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc I ◽  
Mhc Ii ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway

scholarly journals Myeloid and Plasmacytoid Dendritic Cells and Cancer – New Insights

2019 ◽  
Vol 7 (19) ◽  
pp. 3324-3340 ◽  
Author(s):  
Maya Gulubova ◽  
Koni Vancho Ivanova ◽  
Mehmed Hadzhi ◽  
Dimitur Chonov ◽  
Maria Magdalena Ignatova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Mhc I ◽  
Cross Presentation ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
T Helpers

Dendritic cells (DCs) use effective mechanisms to combat antigens and to bring about adaptive immune responses through their ability to stimulate nӓive T cells. At present, four major cell types are categorised as DCs: Classical or conventional (cDCs), Plasmacytoid (pDCs), Langerhans cells (LCs), and monocyte-derived DCs (Mo-DCs). It was suggested that pDCs, CD1c+ DCs and CD141+ DCs in humans are equivalent to mouse pDCs, CD11b+ DCs and CD8α+ DCs, respectively. Human CD141+ DCs compared to mouse CD8α+ DCs have remarkable functional and transcriptomic similarities. Characteristic markers, transcription factors, toll-like receptors, T helpers (Th) polarisation, cytokines, etc. of DCs are discussed in this review. Major histocompatibility complex (MHC) I and II antigen presentation, cross-presentation and Th polarisation are defined, and the dual role of DCs in the tumour is discussed. Human DCs are the main immune cells that orchestrate the immune response in the tumour microenvironment.

scholarly journals TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation

2014 ◽  
Vol 111 (43) ◽  
pp. 15508-15513 ◽  
Author(s):  
A. R. Mantegazza ◽  
A. L. Zajac ◽  
A. Twelvetrees ◽  
E. L. F. Holzbaur ◽  
S. Amigorena ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Presentation ◽  
Cross Talk ◽  
Mhc Ii

scholarly journals Modular expression analysis reveals functional conservation between human Langerhans cells and mouse cross-priming dendritic cells

2015 ◽  
Vol 212 (5) ◽  
pp. 743-757 ◽  
Author(s):  
Maxim N. Artyomov ◽  
Adiel Munk ◽  
Laurent Gorvel ◽  
Daniel Korenfeld ◽  
Marina Cella ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Therapeutic Target ◽  
Langerhans Cells ◽  
Antigen Processing ◽  
Genome Project ◽  
Cross Presentation ◽  
Functional Conservation ◽  
Transcriptional Signature

Characterization of functionally distinct dendritic cell (DC) subsets in mice has fueled interest in whether analogous counterparts exist in humans. Transcriptional modules of coordinately expressed genes were used for defining shared functions between the species. Comparing modules derived from four human skin DC subsets and modules derived from the Immunological Genome Project database for all mouse DC subsets revealed that human Langerhans cells (LCs) and the mouse XCR1+CD8α+CD103+ DCs shared the class I–mediated antigen processing and cross-presentation transcriptional modules that were not seen in mouse LCs. Furthermore, human LCs were enriched in a transcriptional signature specific to the blood cross-presenting CD141/BDCA-3+ DCs, the proposed equivalent to mouse CD8α+ DCs. Consistent with our analysis, LCs were highly adept at inducing primary CTL responses. Thus, our study suggests that the function of LCs may not be conserved between mouse and human and supports human LCs as an especially relevant therapeutic target.

scholarly journals Predominant Role for Directly Transfected Dendritic Cells in Antigen Presentation to CD8+ T Cells after Gene Gun Immunization

1998 ◽  
Vol 188 (6) ◽  
pp. 1075-1082 ◽  
Author(s):  
Angel Porgador ◽  
Kari R. Irvine ◽  
Akiko Iwasaki ◽  
Brian H. Barber ◽  
Nicholas P. Restifo ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Cytotoxic T Cell ◽  
Gene Gun ◽  
Cross Presentation

Cutaneous gene (DNA) bombardment results in substantial expression of the encoded antigen in the epidermal layer as well as detectable expression in dendritic cells (DC) in draining lymph nodes (LNs). Under these conditions, two possible modes of DC antigen presentation to naive CD8+ T cells might exist: (a) presentation directly by gene-transfected DC trafficking to local lymph nodes, and (b) cross-presentation by untransfected DC of antigen released from or associated with transfected epidermal cells. The relative contributions of these distinct modes of antigen presentation to priming for cytotoxic T cell (CTL) responses have not been clearly established. Here we show that LN cells directly expressing the DNA-encoded antigen are rare; 24 h after five abdominal skin bombardments, the number of these cells does not exceed 50–100 cells in an individual draining LN. However, over this same time period, the total number of CD11c+ DC increases more than twofold, by an average of 20,000–30,000 DC per major draining node. This augmentation is due to gold bombardment and is independent of the presence of plasmid DNA. Most antigen-bearing cells in the LNs draining the site of DNA delivery appear to be DC and can be depleted by antibodies to an intact surface protein encoded by cotransfected DNA. This finding of predominant antigen presentation by directly transfected cells is also consistent with data from studies on cotransfection with antigen and CD86-encoding DNA, showing that priming of anti-mutant influenza nucleoprotein CTLs with a single immunization is dependent upon coexpression of the DNAs encoding nucleoprotein and B7.2 in the same cells. These observations provide insight into the relative roles of direct gene expression and cross-presentation in CD8+ T cell priming using gene gun immunization, and indicate that augmentation of direct DC gene expression may enhance such priming.

scholarly journals Dendritic cells trigger imbalance of Th1/Th2 cells in silica dust exposure rat model via MHC-II, CD80, CD86 and IL-12

RSC Advances ◽  
2018 ◽  
Vol 8 (46) ◽  
pp. 26108-26115 ◽  
Author(s):  
Lei Bao ◽  
Changfu Hao ◽  
Suna Liu ◽  
Lin Zhang ◽  
Juan Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Antigen Presentation ◽  
Rat Model ◽  
Crucial Role ◽  
Dust Exposure ◽  
Th2 Cells ◽  
Mhc Ii ◽  
Silica Dust

Dendritic cells (DCs), the most powerful antigen presentation cell (APC) in the immune response, play a crucial role in silicosis.

scholarly journals Expression of the transcription factor cKrox in peripheral CD8 T cells reveals substantial postthymic plasticity in CD4-CD8 lineage differentiation

2007 ◽  
Vol 204 (2) ◽  
pp. 267-272 ◽  
Author(s):  
S. Rhiannon Jenkinson ◽  
Andrew M. Intlekofer ◽  
Guangping Sun ◽  
Lionel Feigenbaum ◽  
Steven L. Reiner ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Cd8 T Cells ◽  
Mhc I ◽  
Mhc Ii ◽  
Lineage Differentiation ◽  
Effector Genes ◽  
Histocompatibility Complex ◽  
Helper Function ◽  
Cytotoxic Function

Most T cells belong to either of two lineages defined by the mutually exclusive expression of CD4 and CD8 coreceptors: CD4 T cells are major histocompatibility complex (MHC) II restricted and have helper function, whereas CD8 T cells are MHC I restricted and have cytotoxic function. The divergence between these two lineages occurs during intrathymic selection and is thought to be irreversible in mature T cells. It is, however, unclear whether the CD4-CD8 differentiation of postthymic T cells retains some level of plasticity or is stably maintained by mechanisms distinct from those that set lineage choice in the thymus. To address this issue, we examined if coreceptor or effector gene expression in mature CD8 T cells remains sensitive to the zinc finger transcription factor cKrox, which promotes CD4 and inhibits CD8 differentiation when expressed in thymocytes. We show that cKrox transduction into CD8 T cells inhibits their expression of CD8 and cytotoxic effector genes and impairs their cytotoxic activity, and that it promotes expression of helper-specific genes, although not of CD4 itself. These observations reveal a persistent degree of plasticity in CD4-CD8 differentiation in mature T cells.

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