Adaptive immunity II Flashcards

1
Q

What happens to T cells in the thymus?

A
  • Undergo early developmental processes to generate T cells expressional clonal TCR (T cell receptor)
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2
Q

What are CD4 and CD8?

A
  • Glycoproteins
  • Serve as a co-receptor for T cell receptors
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3
Q

What does CD4 TCR do?

A
  • Recognises MHC II/peptide complex
  • Forms a bridge between the CD4 on TCR and MHC II/peptide complex
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4
Q

What does CD8 TCR do?

A
  • Recognises MHC I/peptide complex
  • Forms a ‘bridge’ between the CD8 on TCR and MHC I/peptide complex
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5
Q

What does the MHC I present?

A
  • Endogenous antigen
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6
Q

What does the MHC II present?

A
  • Exogenous antigen
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7
Q

How do T cells recirculate and become activated? What 3 signals activate naive T cells?

A

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
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8
Q

Where are naive T cells activated?

A
  • Secondary lymphoid organs (spleen etc)
  • Naive T cells circulate through lymph nodes finding antigens that will activate them
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9
Q

What lymphocytes are APCs?

A
  • B lymphocytes
  • Macrophages
  • Dendritic cell
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10
Q

What are the main roles of CTL cells?

A
  • CTL (Cytotoxic T lymphocyte) T cells express CD8
  • Kills cells infected with microbes
  • Kill tumour cells
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11
Q

How are MHCs formed?

A

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

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12
Q

How do T cells recognise antigens?

A
  • 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
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13
Q

How are antigens recognised by other immune cells?

A
  • 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
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14
Q

Describe MHC class I and its structure

A
  • 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

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15
Q

Describe MHC class II and its structure

A
  • 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

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16
Q

Describe the structure of the T cell receptor

A
  • 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
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17
Q

How do antibodies work?

A

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)
18
Q

What does cell mediated immunity fight?

A

Intracellular microbes:
- Intracellular bacteria in phagosomes of phagocytes
- Viruses in cytoplasm in phagocytes of non-phagocytotic cells
- Parasite = both intra + extracellular

19
Q

What do T cell receptors recognise?

A

Residues from MHC and residues from the peptide

20
Q

What do delta-gamma T cells recognise?

A

Antigens not displaced by MHC I and MHC II (are not MHC restricted)

21
Q

What is an endogenous pathogen?

A
  • An infection caused by an infectious agent that is present on or in the host prior to the start of the infection
22
Q

What is an exogenous pathogen?

A
  • Occur when a pathogen enters a patient’s body from their environment
23
Q

How are endogenous pathogens processed and presented to CD8+ cells?

A
  • 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
24
Q

How are exogenous pathogens processed and presented by CD4+ cells?

A
  • 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
25
Q

What is the role of dendritic cells?

A
  • 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
26
Q

Outline the 3 signals for different types of T cell activation

A
  • 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
27
Q

Describe the main types of T cell mediated responses and a summary of their roles

A
  • 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

28
Q

What is the main cytokine of Th1?

A

Main cytokine = IFNγ

29
Q

What are the main roles of Th1?

A
  • Activate phagocytes (macrophages) = increased destruction of intracellular pathogens - Does this by secreting cytokine
  • Stimulate production of IgG Abs = increased phagocytosis of microbes
30
Q

What are some Th1 -mediated diseases?

A
  • Granulomas
  • Autoimmune diseases
31
Q

How does Th1 induce macrophage activation if microbes block phagocytosis?

A

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)

32
Q

What is Th1 mediated macrophage activation?

A
  • 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)
33
Q

What is the main role of Th2?

A
  • Response against infections with helminths, too large to phagocytose and resistant to microbicidal activities of macrophages
34
Q

How does Th2 help B cells?

A

Help B cells produce antibodies which:
- Opsonise helminths
- Activate eosinophils/mast cells which destroy helminths

35
Q

Outline the cytokines important to Th2 and their roles

A
  • 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
36
Q

Outline the cytokines important to Th17

A
  • IL 17- chemokine production = neutrophil production, also production of anti-microbial substances (defensins)
  • IL 22 - increased barrier function of epithelia
  • IL-17F
37
Q

Where are Th17 normally found?

A
  • Present predominantly in mucosa (GI tract) and defence against intestinal infections by recruiting neutrophils to site of infection
38
Q

How does Th17 respond against infection?

A

Th17 responses against extracellular bacteria and fungi mainly by promoting neutrophil-mediated inflammation

39
Q

How does Th17 collaborate with Th1?

A

IN phagocyte-mediated CMI-Th17 recruit neutrophils and monocytes to site, Th1 cells activate phagocytes

40
Q

What are some of the suppression mechanisms Treg use?

A

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)
41
Q

What are some CD8+ CTL-mediated immune responses?

A

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