Innate Immunity Flashcards
What is cross-presentation
The process where dendritic cells (DCs) present extracellular antigens on MHC class I to CD8 T cells, initiating a cytotoxic T cell response.
What happens to a DC when infected by a pathogen
An infected dendritic cell becomes dysfunctional, does not migrate to the lymph nodes, and thus fails to present antigens to CD8+ T cells, impairing the adaptive immune response initiation.
Markers of Cross-presenting DCs in Mice
Cross-presenting DCs in mice are identified by the expression of surface molecules such as CD24, Clec9A, XCR-1, and CD8α.
Role of Infected Tissue Cells in Immune Response
Infected tissue cells process pathogen or viral antigens internally but cannot effectively present these antigens to CD8+ T cells, failing to initiate an immune response
Function of Cross-Presenting Dendritic Cells
Specialized in capturing and processing antigens from infected cells or tissues through a unique pathway for presentation on MHC class I molecules and migrating to lymph nodes for T cell activation.
How does Cross-Presentation activate CD8+ T cells?
Cross-presenting DC presents antigens to CD8+ T cells in lymph nodes, activating them to seek and destroy cells infected with the same pathogen, crucial for fighting viral infections and tumour immunity
How do T cells recognise antigens?
T cells recognise antigens as short, linear sequences of amino acids presented on MHC molecules.
MHC Class I
MHC Class I presents endogenous antigens to CD8+ T cells
How are proteins processed for Class II MHC presentation?
Proteins are taken up into endocytic vesicles, degraded in acidic multilamellar bodies by enzymes like cathepsins, generating peptides
Role of Acidic Proteases in Antigen Processing
Acidic proteases like cathepsin L or S generate peptides from antigen proteins, crucial for MHC class II antigen presentation.
Function of GILT in Antigen Processing
GILT breaks disulfate bonds
Function of AEP in Antigen Processing
AEP unlocks tertiary structures, enhancing antigen processing for MHC presentation
MHC class II
MHC Class II presents exogenous antigens to CD4+ T cells.
Roles do CIIV play in antigen processing and presentation
Sorting compartment -newly internalized antigens meet MHC for peptide loading, less acidic to facilitate this interaction (than late endosomal)
Roles do MIIC play in antigen processing and presentation
MIIC is an advanced, late-stage compartment for final antigen processing; its acidic environment optimizes protease activity for peptide generation.
What is the function of the invariant chain in MHC class II processing?
Invariant chain guides MHC II through the ER and Golgi to endosomal compartments, preventing premature peptide binding by occupying the peptide-binding groove with its CLIP region, ensuring proper MHC II folding and transport.
Describe the sorting signals within the invariant chain that direct MHC class II
contains dileucine, tyrosine-based, and di-acidic motifs as sorting signals, directing MHC class II molecules from the ER through the Golgi to endosomal/lysosomal compartments for antigen processing.
How does HLA-DM facilitate MHC class II processing?
HLA-DM removes CLIP from the MHC II groove, stabilizing the complex for high-affinity peptide loading onto the peptide-binding groove (PBG), ensuring that MHC II presents the most immunogenically potent peptides.
What leads to B cell anergy and its significance?
B cell anergy occurs when B cells bind self-antigen but don’t receive T cell help, preventing autoantibody production and autoimmunity by making the B cell functionally unresponsive.
How do viruses interfere with MHC class II processing?
Viruses may inhibit class II molecule expression, interfere with MHC II trafficking, or disrupt viral antigen processing, evading detection and impeding the adaptive immune response.
MHC II chain synthesis
alpha and beta, which are synthesized in the ER where they bind to the invariant chain, facilitating the folding and prevention of binding to the ER.
Invariant chain guide
MHC II molecules through the Golgi apparatus to the endosomal/lysosomal compartments
CLIP
maintaining the integrity of the peptide binding groove during transport.
anergy/ anagenic
prevents immune cells from attacking host tissues
Viral Interference with MHC II processing
inhibit the expression of class II molecule
interfere with intracellular trafficking of MHC class II
disrupt the normal processing of viral antigens that should be loaded.
What does the surface expression of pMHC indicate in antigen-presenting cells?
Surface expression of pMHC indicates that MHC class II molecules have processed and bound a peptide and are displayed on the surface of an APC for T cell recognition.
How do dendritic cells balance MHC class II molecules and pMHC surface expression in a steady state?
In the steady state, DCs balance new MHC class II synthesis with surface pMHC expression through recycling, avoiding unnecessary T cell activation and autoimmunity.
Why are B cells considered efficient in antigen presentation via MHC class II?
B cells, being MHC II+, have a low rate of ubiquitination and can efficiently present antigens internalized through their B cell receptor, making them more effective than other APCs.
ubiquitination
Ubiquitination is a cellular process where a ubiquitin protein is covalently attached to a target protein
Describe the components and functions of the regulatory particles (19S or PA700) of the proteasome.
Regulatory particles are cap-like structures responsible for recognizing polyubiquitinated proteins, unfolding them, and translocating them into the core for degradation. They include a base with ATPases for energy and a lid for ubiquitin removal.
What are the regulatory particles of the proteasome
19S or PA700
Describe the efficiency of the MHC class I antigen presentation process
The process is rapid but relatively inefficient, with only a small proportion of total protein molecules being presented.
What is the structure of the core particle (20S Proteasome)?
The core particle is a barrel-shaped structure with four stacked rings: two outer alpha rings and two inner beta rings, with only the beta rings having proteolytic sites
what is the core particle of the proteasome
20S
Function of
Ubiquitination
Ubiquitination regulates various cellular processes, including protein degradation by the proteasome, signal transduction pathways, cell cycle control, DNA repair mechanisms, and immune responses.
How does ubiquitination signal for protein degradation?
Proteins tagged with a polyubiquitin chain are recognized and degraded by the proteasome. This process removes damaged, misfolded, or unnecessary proteins from the cell.
What is the structure of the B cell receptor (BCR)
membrane-bound immunoglobulin molecule that recognizes antigens and an associated heterodimer of Ig-alpha and Ig-beta proteins, which transduce signals into the cell upon antigen binding.
How does the BCR recognize antigens?
BCR recognizes antigens through its variable region, which can bind to a specific part of an antigen called an epitope. This interaction triggers B cell activation and the immune response.
How do B cells present antigens to T cells?
After antigen binding, B cells internalize the BCR-antigen complex via endocytosis. The antigen is processed and presented on MHC class II molecules to T helper cells, leading to B cell activation and antibody production.
What happens when the BCR is engaged by its specific antigen?
B cell activation, proliferation, and differentiation into plasma cells that secrete antibodies or memory B cells.
What is the significance of the low rate of ubiquitination in B cells?
preserve the BCR and MHC class II molecules on the cell surface, ensuring effective antigen presentation and sustained interaction with T helper cells.
What is monoubiquitination and its typical outcomes for substrate proteins?
Attaching a single ubiquitin molecule to the substrate protein. This modification can affect protein activity, location, or interactions
What are the implications of ubiquitination in diseases?
Aberrations in ubiquitination processes can lead to diseases, including cancer, neurodegenerative disorders, and immune system dysfunctions. For example, malfunction in the degradation of cell cycle regulators can contribute to cancer, while impaired degradation of proteins can lead to conditions like Parkinson’s disease.
How do immunoproteasomes differ from standard proteasomes?
Immunoproteasomes have slightly different subunits in the beta rings specialized for generating peptides for MHC Class I presentation, enhancing the immune response.
Standard Proteosome structure
beta subunits β1, β2, and β5 responsible for caspase-like, trypsin-like, and chymotrypsin-like proteolytic activities
Immunoproteasomes structure
they replace the subunits with β1i, β2i, and β5i, altering the cleavage specificity to produce peptides more suitable for MHC Class I presentation.
What triggers the formation of immunoproteasomes?
Immunoproteasomes are induced by interferon-gamma (IFN-γ) during immune responses, particularly under conditions of inflammation or infection, enhancing the cell’s ability to present antigens and stimulate CD8+ T cell responses.
What role do immunoproteasomes play in antigen presentation?
optimize the peptides for binding to MHC Class I molecules, facilitating efficient recognition by CD8+ T cells and enhancing the cellular immune response.
How are immunoproteasomes relevant to diseases?
implicated in autoimmune diseases, where their altered peptide processing may lead to the presentation of autoantigens. They also play a role in cancer immunity, where enhancing their activity could improve antigen presentation and tumor cell recognition by the immune system.
What is the significance of immunoproteasome inhibitors?
therapeutic agents for autoimmune diseases by potentially reducing the presentation of autoantigens. They may also affect cancer treatment by altering the immune system’s ability to recognize and destroy cancer cells.
autoantigens
normal proteins or molecules found within the body that are mistakenly recognized as foreign by the immune system, leading to an autoimmune response.
how does autoantigens occur
Molecular Mimicry, post-translational modifications, Loss of Immune Regulation, Genetic Susceptibility (HLA types), enviromental triggers (altered self antigens)
Describe the structure and roles of the alpha and beta subunits in the proteasome
Alpha subunits form the gate to the proteasome’s inner chamber where beta subunits, containing protease activities, degrade proteins into peptides. ATPases facilitate substrate unfolding and entry.
What is the typical length of peptides processed by the proteasome for MHC I presentation, and how are they further trimmed?
Proteasome generates peptides 8-10 amino acids long, which can extend up to 25 amino acids. Aminopeptidases in the cytosol further trim peptides for MHC I presentation.
Describe the TAP complex’s role in antigen processing for MHC I.
TAP1 and TAP2 form a complex that transports cytosolic peptides into the ER, using ATP for translocation. The complex is upregulated by interferons and associates with tapasin to optimize peptide loading onto MHC I.
What is the role of calnexin, calreticulin
Calnexin and calreticulin bind to MHC I molecules for proper folding
Role of Tapasin
Tapasin bridges MHC I to TAP and ensures high-affinity peptide loading
role of Erp57
Erp57 works with tapasin to aid folding.
Explain the role of tapasin’s N-terminal in MHC I peptide loading
Tapasin’s N-terminal connects to the alpha2 and alpha3 domains of MHC I and is vital for high-affinity peptide loading. It is a transmembrane glycoprotein located on the ER.
How does tapasin contribute to the optimization of MHC I peptide loading
Tapasin acts as a bridge between TAP and MHC I, working with Erp57 to optimize peptide loading and enhance the immune response.
What is the function of ERAP-1 in MHC class I antigen processing?
ERAP-1 trims peptides within the ER to the optimal length for binding to the MHC class I peptide-binding groove, crucial for creating epitopes recognized by T cells. It is inducible by IFN-γ.
Describe the process of MHC class I molecule surface expression post-peptide loading.
After peptide loading, the pMHC I complex is transported to the cell surface via the Golgi, where it can be recognized by CD8+ T cells, triggering an immune response
How can viruses interfere with MHC class I pathways, and what role does brefeldin A play?
Viruses may evade immune detection by downregulating peptide loading complexes or degrading MHC class I molecules. Brefeldin A, a drug, can inhibit MHC class I transport from the Golgi to the ER, highlighting the pathway’s significance, especially in the context of cancer research
Where is polymorphism most common in MHC class I molecules
Variation or polymorphism in MHC class I molecules typically occurs in the peptide-binding groove, influencing the range of peptides that can bind.
Explain the process and significance of cross-priming by dendritic cells
Cross-priming involves dendritic cells presenting peptides on MHC class I that are typically presented on MHC class II, initiating a CD8+ T cell response. It enables CD8+ T cell activation against pathogens not directly infecting APCs and is critical for robust immunity.
Why is cross-presentation crucial for the immune response?
Cross-presentation allows dendritic cells to process and present exogenous antigens from non-APC-infected cells or tumors on MHC class I, broadening the immune response to include CD8+ T cells against diverse pathogens.
