Adaptive immunity II Flashcards
What happens to T cells in the thymus?
- Undergo early developmental processes to generate T cells expressional clonal TCR (T cell receptor)
What are CD4 and CD8?
- Glycoproteins
- Serve as a co-receptor for T cell receptors
What does CD4 TCR do?
- Recognises MHC II/peptide complex
- Forms a bridge between the CD4 on TCR and MHC II/peptide complex
What does CD8 TCR do?
- Recognises MHC I/peptide complex
- Forms a ‘bridge’ between the CD8 on TCR and MHC I/peptide complex
What does the MHC I present?
- Endogenous antigen
What does the MHC II present?
- Exogenous antigen
How do T cells recirculate and become activated? What 3 signals activate naive T cells?
Recirculation - mechanism by which T cells pass through peripheral sites to find antigens, returning via the lymphatics back into circulation until they find the antigen that activates them
Resting naive T cells activated by integration of 3 signals:
- Antigen recognition
- Co-stimulation
- Cytokines
Where are naive T cells activated?
- Secondary lymphoid organs (spleen etc)
- Naive T cells circulate through lymph nodes finding antigens that will activate them
What lymphocytes are APCs?
- B lymphocytes
- Macrophages
- Dendritic cell
What are the main roles of CTL cells?
- CTL (Cytotoxic T lymphocyte) T cells express CD8
- Kills cells infected with microbes
- Kill tumour cells
How are MHCs formed?
MHC molecules are made by antigen presenting cells (APCs)
APCs process antigens into peptides (for most T cells), these ARE the MHC proteins
Peptides bind to MHC molecules
Peptide/MHC complexes presented on APC surface = activation of T cells for specific antigenic peptide
How do T cells recognise antigens?
- TCR in T cell recognises antigen presented in context of MHC:
- CD4 TCR recognises antigens displayed by MHC II/peptide complex
- CD8 TCR recognises antigens displayed by MHC I/ peptide complex
How are antigens recognised by other immune cells?
- Immunoglobulins on B cells and T cell receptors on T cells recognise any microbial structure
- Distinguish between antigens on different and same microbes
- Self-non-self discrimination can fail = autoimmune disease
- B cells recognise antigens (soluble or cell bound) directly but T cells can’t
Describe MHC class I and its structure
- Present in all nucleate cells (including professional APCs)
- Continuous sampling of peptides from within the cells (cytosol) - endogenous antigens
- For this reason MHC I tends to present viral antigens
- Recognised by CD8+ CTL
Structure:
- Ternary complexes of the soluble serum protein beta 2-microglobulin, MHC heavy chain, and bond peptide
- The first 2 domains (alpha 1 and alpha 2) of the heavy chain create the peptide binding left and the surface that contacts the T-cell receptor
- The alpha 3 domain interacts with the CD8 co-receptor of T cells, holds MHC I molecule in place
Describe MHC class II and its structure
- Present on professional APCs only (e.g. mononuclear phagocytes, dendritic cells)
- APCs engulf and break up pathogens from outside the cell, presents broken-up peptides on MHC class II from intracellular vesicles
- For this reason MHC II tends to present bacterial antigens
- Recognised by CD4+ Th cells
Structure:
- Heterodimers composed of an alpha and a beta chain
- Both the alpha and beta chain are made up of 2 domains , alpha 1 and 2 and beta 1 and 2
- The alpha 1 and beta 1 domains create the peptide binding cleft
Describe the structure of the T cell receptor
- 2 polypeptide chains together forming one antigen binding region linked by disulphide bonds
- 95% of TCRs are composed of an alpha + beta chain (variable domain at top, constant domain at bottom)
- 5% composed of gamma and delta chains
How do antibodies work?
Bind to extracellular microbes and toxins and:
- Neutralise microbes (prevent binding of antigen to receptors/cells, blocking entry and its effects on cells)
- Eliminate microbes through opsonisation (increases phagocytosis) and complement activation (opsonisation and lysis of microbe)
What does cell mediated immunity fight?
Intracellular microbes:
- Intracellular bacteria in phagosomes of phagocytes
- Viruses in cytoplasm in phagocytes of non-phagocytotic cells
- Parasite = both intra + extracellular
What do T cell receptors recognise?
Residues from MHC and residues from the peptide
What do delta-gamma T cells recognise?
Antigens not displaced by MHC I and MHC II (are not MHC restricted)
What is an endogenous pathogen?
- An infection caused by an infectious agent that is present on or in the host prior to the start of the infection
What is an exogenous pathogen?
- Occur when a pathogen enters a patient’s body from their environment
How are endogenous pathogens processed and presented to CD8+ cells?
- Virus free in cytosol replicates its viral proteins
- Viral proteins undergo ubiquination (tagged with ubiquitin)
- This targets it to be degraded by proteasome breaking down the proteins into peptides in cytosol (hence endogenous)
- Peptides transported into ER where they’re further broken down to fit better in MHC I
- Assembly of MHC I-peptide complex in ER
- MHC I-peptide complex transported to membrane and presented - recognised by CD8+ T cells
How are exogenous pathogens processed and presented by CD4+ cells?
- Uptake of extracellular proteins into vesicular components of antigen presenting cell
- Processing of internalised proteins in endosomal/lysosomal vesicles
- Biosynthesis and transport of MHC II molecules other than endosomes
- Association of processed peptides with class II MHC molecules in vesicles
- Expression of peptide- MHC complexes on cell surface, binds to CD4+ Th cell
What is the role of dendritic cells?
- Sentinel cells on skin, mucosa + tissues which capture microbes, phagocytose, and process pathogens and present antigens to T cells
- Also increase expression of co-stimulation = tells T cells about infection, they can migrate to naive T cells in lymph nodes and find the specific T cell that needs to be activated
Outline the 3 signals for different types of T cell activation
- To activate T cells = MHC presents antigen to T cell receptor (TCR)
- For naive T cells = Signal 2, co-stimulation through co-stimulating molecule (CD80//CD86) on APC interact with CD28 on T cell - This will strengthen the bond between the antigen and T cell
- 3rd signal is cytokines - APC secretes cytokines to signal T cell
Describe the main types of T cell mediated responses and a summary of their roles
- Th1 (CD4+) - help phagocytose kill ingested microbes
- Th2 (CD4+) - help eosinophils/mast cells kill helminths
- Th17 (CD4+) - defence against bacteria + fungi
- CTL (CD8+) - kill cells infected by microbes that grow in cytosol
Regulatory T cells (CD4+, CD25+, FOXP3+) - inhibit immune response
What is the main cytokine of Th1?
Main cytokine = IFNγ
What are the main roles of Th1?
- Activate phagocytes (macrophages) = increased destruction of intracellular pathogens - Does this by secreting cytokine
- Stimulate production of IgG Abs = increased phagocytosis of microbes
What are some Th1 -mediated diseases?
- Granulomas
- Autoimmune diseases
How does Th1 induce macrophage activation if microbes block phagocytosis?
Microbes such as salmonella and mycobacterium may block phagocytosis, so they persist in phagosomes, Th1 hep signals occur to induce macrophage activation:
- Contact mediated signals CD40L - CD40
- Soluble signals IFN-γ
CD40L - CD40 ensures only infected macrophage receive help from Th1 cells = prevent autoimmune responses and inflammation (specificity)
What is Th1 mediated macrophage activation?
- Increased ROS (reactive oxygen species) and NO (nitric oxide)
- Increased lysosomal enzymes = increased killing of phagocytose microbes
- Secretion of cytokines TNF-a, IL-1, IL-12 = local inflammation, increased neutrophils and monocytes recruitment = increased phagocytosis
- Tissue repair - PDGF (fibroblast proliferation), TGF-b (collagen synthesis), FGF (angiogenesis)
What is the main role of Th2?
- Response against infections with helminths, too large to phagocytose and resistant to microbicidal activities of macrophages
How does Th2 help B cells?
Help B cells produce antibodies which:
- Opsonise helminths
- Activate eosinophils/mast cells which destroy helminths
Outline the cytokines important to Th2 and their roles
- IL-4 and IL-13 stimulate IgE production which opsonises helminths
- Eosinophils have IgE receptors which bind to Fc region -IL-5 activates bound eosinophils = kill helminths and release granule content : MBP, MCP = can destroy tough integument of worms
- IgE opsonises helminths, mast cells bind to Fc of IgE = degranulation of mast cells - release vasoactive amines, TNF-a, lipid mediators> local inflammation =destroyparasite
Outline the cytokines important to Th17
- IL 17- chemokine production = neutrophil production, also production of anti-microbial substances (defensins)
- IL 22 - increased barrier function of epithelia
- IL-17F
Where are Th17 normally found?
- Present predominantly in mucosa (GI tract) and defence against intestinal infections by recruiting neutrophils to site of infection
How does Th17 respond against infection?
Th17 responses against extracellular bacteria and fungi mainly by promoting neutrophil-mediated inflammation
How does Th17 collaborate with Th1?
IN phagocyte-mediated CMI-Th17 recruit neutrophils and monocytes to site, Th1 cells activate phagocytes
What are some of the suppression mechanisms Treg use?
Treg = regulatory T cels, regulate immune response, prevents overreaction
- Maintain immune tolerance by suppressing immune responses
- Identified by expression of CD4 and high levels of CD25 and transcription factor FOXD3
- Inhibit effector CD4+ T cells, CD8+ T cells and antigen presenting cells, B cells
Suppression mechanism: - Production of anti-inflammatory cytokines (IL-10, TGF- beta)
- Other mechanisms (dependent on contact with Treg-target cells)
What are some CD8+ CTL-mediated immune responses?
Eliminate intracellular microbes in cytosol by killing infected cells
Important in tumours and organ rejection in transplants
Killing = antigen specific and contact dependent so healthy/uninfected cells not killed
CTL delivers lethal hit, detaches and target will die - release of cytolytic proteins stored in secretory granules which trigger apoptosis in target cell
Cytolytic proteins:
- Perforin = form pores = delivery of granzymes
- Granzymes A, B and C = initiate apoptosis by activating caspases (granzyme B triggers mitochondrial apoptotic pathway)
- Delivered at site of contact = don’t kill neighbouring healthy cells
Also kill by different method:
- FasL on CTL ligates Fas receptor on target cell = activate caspase
