3-D Structure of Multilaminar Lysosomes in Antigen Presenting Cells Reveals Trapping of MHC II on the Internal Membranes

Immunohistochemical analysis of skin and draining lymph nodes of sheep repeatedly infested with the ixodid tickHyalomma anatolicum anatolicumwere studied for different antigen-presenting cells and lymphocyte subpopulations. Infiltration of neutrophils, macrophages and lymphocytes adjacent to the tick bite site were observed. Skin biopsies showed significant increases in dermal infiltration of CD8+and γδ+T cells at 72 h and 8 days after both primary and secondary infestation. Infiltrations of MHC-II DR/DQ decreased at 72 h after tick infestation, whereas significant increases were recorded for 8-day skin biopsies. CD1+cellular infiltrations were observed during secondary infestations at the dermis. Decreased ratios of CD4[ratio ]CD8 T cells and MHC-II[ratio ]CD1 antigen-presenting cells were observed in both infestations compared to healthy skin biopsies. Ratios of αβ[ratio ]γδ T cells increased gradually during infestation compared to uninfested skin. The regional lymph nodes from tick-infested sheep showed an increased CD8+, γδ+T and CD1+cellular infiltration compared to control lymph nodes. CD4+T cells were decreased. There were no significant changes in CD45R+cellular infiltration either at skin lesions or regional lymph nodes.

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Faculty Opinions recommendation of 3-D Structure of multilaminar lysosomes in antigen presenting cells reveals trapping of MHC II on the internal membranes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022087.251690 ◽

2004 ◽

Author(s):

Jean Gruenberg

Keyword(s):

Antigen Presenting Cells ◽

Mhc Ii ◽

Antigen Presenting

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High Level Expression of MHC-II in HPV+ Head and Neck Cancers Suggests that Tumor Epithelial Cells Serve an Important Role as Accessory Antigen Presenting Cells

Cancers ◽

10.3390/cancers11081129 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1129 ◽

Cited By ~ 7

Author(s):

Steven F. Gameiro ◽

Farhad Ghasemi ◽

John W. Barrett ◽

Anthony C. Nichols ◽

Joe S. Mymryk

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Antigen Presentation ◽

Head And Neck ◽

Antigen Presenting Cells ◽

Human Papillomaviruses ◽

Mhc Ii ◽

Hpv Status ◽

Antigen Presenting ◽

The Impact

High-risk human papillomaviruses (HPVs) are responsible for a subset of head and neck squamous cell carcinomas (HNSCC). Expression of class II major histocompatibility complex (MHC-II) is associated with antigen presenting cells (APCs). During inflammation, epithelial cells can be induced to express MHC-II and function as accessory APCs. Utilizing RNA-seq data from over 500 HNSCC patients from The Cancer Genome Atlas, we determined the impact of HPV-status on the expression of MHC-II genes and related genes involved in their regulation, antigen presentation, and T-cell co-stimulation. Expression of virtually all MHC-II genes was significantly upregulated in HPV+ carcinomas compared to HPV− or normal control tissue. Similarly, genes that encode products involved in antigen presentation were also significantly upregulated in the HPV+ cohort. In addition, the expression of CIITA and RFX5—regulators of MHC-II—were significantly upregulated in HPV+ tumors. This coordinated upregulation of MHC-II genes was correlated with higher intratumoral levels of interferon-gamma in HPV+ carcinomas. Furthermore, genes that encode various co-stimulatory molecules involved in T-cell activation and survival were also significantly upregulated in HPV+ tumors. Collectively, these results suggest a previously unappreciated role for epithelial cells in antigen presentation that functionally contributes to the highly immunogenic tumor microenvironment observed in HPV+ HNSCC.

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IFNα treatment generates antigen-presenting cells insensitive to atorvastatin inhibition of MHC-II expression

Clinical Immunology ◽

10.1016/j.clim.2008.07.010 ◽

2008 ◽

Vol 129 (2) ◽

pp. 350-359 ◽

Cited By ~ 5

Author(s):

Patricia López ◽

Carmen Gutiérrez ◽

Ana Suárez

Keyword(s):

Antigen Presenting Cells ◽

Mhc Ii ◽

Antigen Presenting

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Persistence of Zinc-Binding Bacterial Superantigens at the Surface of Antigen-Presenting Cells Contributes to the Extreme Potency of These Superantigens as T-Cell Activators

Infection and Immunity ◽

10.1128/iai.73.9.5358-5366.2005 ◽

2005 ◽

Vol 73 (9) ◽

pp. 5358-5366 ◽

Cited By ~ 11

Author(s):

Dorothy D. Pless ◽

Gordon Ruthel ◽

Emily K. Reinke ◽

Robert G. Ulrich ◽

Sina Bavari

Keyword(s):

T Cell ◽

Binding Site ◽

Antigen Presenting Cells ◽

Subcellular Fractionation ◽

Zinc Binding ◽

Toxic Shock ◽

Mhc Ii ◽

Human B Cells ◽

Class Ii Mhc ◽

Antigen Presenting

ABSTRACT Bacterial superantigen intoxication causes massive overactivation of T cells, which can result in potentially lethal toxic shock. Superantigens fall into two groups: superantigens such as staphylococcal enterotoxin B (SEB) that contain a single generic binding site for major histocompatibility complex class II (MHC-II) and more potent superantigens such as SEA with a second, zinc-dependent MHC-II binding site that enables them to cross-link adjacent MHC-II molecules. We found that although all superantigens bound rapidly to the surface of human B cells, zinc-binding superantigens largely remained at the cell surface for at least 40 h. In contrast, single-binding-site superantigens were greatly depleted from the surface by 4 h. Subcellular fractionation and confocal microscopy revealed that some SEB entered lysosomal compartments, but SEA remained almost undetectable inside cells at 20 h. SEA and SEB mutants that do not bind MHC-II were trafficked rapidly to lysosomal compartments. Our findings suggest that the persistence of SEA and other zinc-dependent, cross-linking superantigens on the surface of antigen-presenting cells contributes to their potency as T-cell activators.

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Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain

Journal of Neuroinflammation ◽

10.1186/s12974-020-01776-7 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 9

Author(s):

Jinar Rostami ◽

Grammatiki Fotaki ◽

Julien Sirois ◽

Ropafadzo Mzezewa ◽

Joakim Bergström ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

T Cell Activation ◽

Cell Activation ◽

Antigen Presenting Cells ◽

Human Microglia ◽

Mhc Ii ◽

Human Astrocytes ◽

Antigen Presenting

Abstract Background Many lines of evidence suggest that accumulation of aggregated alpha-synuclein (αSYN) in the Parkinson’s disease (PD) brain causes infiltration of T cells. However, in which ways the stationary brain cells interact with the T cells remain elusive. Here, we identify astrocytes as potential antigen-presenting cells capable of activating T cells in the PD brain. Astrocytes are a major component of the nervous system, and accumulating data indicate that astrocytes can play a central role during PD progression. Methods To investigate the role of astrocytes in antigen presentation and T-cell activation in the PD brain, we analyzed post mortem brain tissue from PD patients and controls. Moreover, we studied the capacity of cultured human astrocytes and adult human microglia to act as professional antigen-presenting cells following exposure to preformed αSYN fibrils. Results Our analysis of post mortem brain tissue demonstrated that PD patients express high levels of MHC-II, which correlated with the load of pathological, phosphorylated αSYN. Interestingly, a very high proportion of the MHC-II co-localized with astrocytic markers. Importantly, we found both perivascular and infiltrated CD4+ T cells to be surrounded by MHC-II expressing astrocytes, confirming an astrocyte T cell cross-talk in the PD brain. Moreover, we showed that αSYN accumulation in cultured human astrocytes triggered surface expression of co-stimulatory molecules critical for T-cell activation, while cultured human microglia displayed very poor antigen presentation capacity. Notably, intercellular transfer of αSYN/MHC-II deposits occurred between astrocytes via tunneling nanotubes, indicating spreading of inflammation in addition to toxic protein aggregates. Conclusions In conclusion, our data from histology and cell culture studies suggest an important role for astrocytes in antigen presentation and T-cell activation in the PD brain, highlighting astrocytes as a promising therapeutic target in the context of chronic inflammation.

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Trogocytosis of peptide–MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615973114 ◽

2017 ◽

Vol 114 (5) ◽

pp. 1111-1116 ◽

Cited By ~ 50

Author(s):

Kensuke Miyake ◽

Nozomu Shiozawa ◽

Toshihisa Nagao ◽

Soichiro Yoshikawa ◽

Yoshinori Yamanishi ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Differentiation ◽

Cell Surface ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Gm Csf ◽

Mhc Ii ◽

Th2 Cell ◽

Antigen Presenting

Th2 immunity plays important roles in both protective and allergic responses. Nevertheless, the nature of antigen-presenting cells responsible for Th2 cell differentiation remains ill-defined compared with the nature of the cells responsible for Th1 and Th17 cell differentiation. Basophils have attracted attention as a producer of Th2-inducing cytokine IL-4, whereas their MHC class II (MHC-II) expression and function as antigen-presenting cells are matters of considerable controversy. Here we revisited the MHC-II expression on basophils and explored its functional relevance in Th2 cell differentiation. Basophils generated in vitro from bone marrow cells in culture with IL-3 plus GM-CSF displayed MHC-II on the cell surface, whereas those generated in culture with IL-3 alone did not. Of note, these MHC-II–expressing basophils showed little or no transcription of the corresponding MHC-II gene. The GM-CSF addition to culture expanded dendritic cells (DCs) other than basophils. Coculture of basophils and DCs revealed that basophils acquired peptide–MHC-II complexes from DCs via cell contact-dependent trogocytosis. The acquired complexes, together with CD86, enabled basophils to stimulate peptide-specific T cells, leading to their proliferation and IL-4 production, indicating that basophils can function as antigen-presenting cells for Th2 cell differentiation. Transfer of MHC-II from DCs to basophils was also detected in draining lymph nodes of mice with atopic dermatitis-like skin inflammation. Thus, the present study defined the mechanism by which basophils display MHC-II on the cell surface and appears to reconcile some discrepancies observed in previous studies.

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Preclinical Efficacy of a Trivalent Human FcγRI-Targeted Adjuvant-Free Subunit Mucosal Vaccine against Pulmonary Pneumococcal Infection

Vaccines ◽

10.3390/vaccines8020193 ◽

2020 ◽

Vol 8 (2) ◽

pp. 193

Author(s):

Sudeep Kumar ◽

Raju Sunagar ◽

Edmund J. Gosselin

Keyword(s):

Protein A ◽

Pneumococcal Infection ◽

Surface Protein ◽

Antigen Presenting Cells ◽

Mucosal Vaccine ◽

Single Chain ◽

Single Chain Antibody ◽

Mhc Ii ◽

Gamma Receptor ◽

Antigen Presenting

Lack of safe and effective mucosal adjuvants has severely hampered the development of mucosal subunit vaccines. In this regard, we have previously shown that immunogenicity of vaccine antigens can be improved by targeting the antigens to the antigen-presenting cells. Specifically, groups of mice immunized intranasally with a fusion protein (Bivalent-FP) containing a fragment of pneumococcal-surface-protein-A (PspA) as antigen and a single-chain bivalent antibody raised against the anti-human Fc-gamma-receptor-I (hFcγRI) elicited protective immunity to pulmonary Streptococcus pneumoniae infection. In order to further enhance the immunogenicity, an additional hFcγRI-binding moiety of the single chain antibody was incorporated. The modified vaccine (Trivalent-FP) induced significantly improved protection against lethal pulmonary S. pneumoniae challenge compared to Bivalent-FP. In addition, the modified vaccine exhibited over 85% protection with only two immunizations. Trivalent-FP also induced S. pneumoniae-specific systemic and mucosal antibodies. Moreover, Trivalent-FP also induced IL-17- and IL-22-producing CD4+ T cells. Furthermore, it was found that the hFcγRI facilitated uptake and presentation of Trivalent-FP. In addition, Trivalent-FP also induced IL-1α, MIP-1α, and TNF-α; modulated recruitment of dendritic cells and macrophages; and induced CD80/86 and MHC-II expression on antigen presenting cells.

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Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1507981112 ◽

2015 ◽

Vol 112 (33) ◽

pp. 10449-10454 ◽

Cited By ~ 40

Author(s):

Kyung-Jin Cho ◽

Even Walseng ◽

Satoshi Ishido ◽

Paul A. Roche

Keyword(s):

B Cells ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Mhc Ii ◽

Class Ii Mhc ◽

Subsequent Degradation ◽

Antigen Presenting

MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide–MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.

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