Immuno T cell Subsets (7/8)
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- the catabolism of protein into peptides inside a host cell
- some peptides will go on to bind to MHC molecule
- a peptide & MHC are presented on the surface of a host cell
- will go on to be recognized by a TCR on either a CD4+ or CD8+ T cell
- pathogens are taken up by specialized host cells, APCs, and are not pathogenic but still foreign
- “harmless” antigens
derived from inside a host cell as a result/product of the cell being infected by a foreign pathogen
exogenous antigen processing
- occurs using MHC class II pathway (eg. dendritic cells, macrophages)
- 1. antigen is taken into acid vesicles & broken down into peptides
- 2. vesicles containing broken down peptides merge with vesicles containing newly synthesized MHC class II molecules
- 3. peptide-MHC class II is presented on the surface of the cell to CD4+ T cells
endogenous antigen processing
- occurs using MHC class I pathway
- 1. antigen catabolized (degraded) in cytoplasm by proteasome
- 2. peptides transported to ER
- 3. peptides associate & selectively bind to newly made MHC class I molecules (still happening in the ER)
- 4. peptide-MHC class I complex moves from the ER to the golgi & is presented on the surface of the cell for interaction w/ CD8+ T cells
What size peptide can bind to an MHC class I complex?
- peptides must be 8-9 amino acids long
- this length fits into the peptide-binding groove of the MHC class I molecule
- there are fewer peptide size restraints in respect to MHC class II molecules (can have 12-20 AA long peptides binding)
What effect does Interferon gamma (IFNγ) have on antigen processing pathways?
- it can up-regulate both MHC class I & II processing
- in contrast, viruses/tumors can down-regulate processing, especially endogenous in MHC class I presenting cells
What happens when an antigen peptide does not bind to an MHC molecule?
it does NOT trigger an immune response
mechanism by which dendritic cells can showcase peptides derived from exogenous antigen processing & present them to CD8+ T cells
What does the selectivity of peptide binding to certain HLA molecules and huge diversity of HLA molecules help to explain?
- upside: the combination of HLA & peptides invoke a protective response in response to certain diseases (eg. malaria)
- downside: the large diversity sometimes confers pathology in those particular individuals who have HLAs that are anti to self peptides
- there's an evolutionary advantage
What is required but not sufficient for an APC to activate a CD4+ T cell?
- MHC class II presenting a peptide expressed on the APC surface
- TWO SIGNALS TOTAL are required for CD4+ T cell activation
- signal #1: MHC class II + peptide --- TCR
- signal #2: between costimulators
- molecules required in addition to the TCR to activate naïve (have not yet encountered antigen) T cells via signal transduction
- costimulators on T cell surface interact with molecules on the surface of an APC to provide a costimulator (2nd signal)
- eg. CD28 (T cell) --- B7 (APC)
- CD40 Ligand/CD40L/CD154 (T cells) --- CD40 (APC)
How do costimulators come about on APC & T cell surfaces?
- APC: induced AFTER exposure to pathogen
- T cell: some up-regulated during response
What is the key APC for the activation of naïve T cells?
the dendritic cell
_______ induce maturation of dendritic cell in tissue
- pathogens induce maturation of dendritic cell in tissues
- phagocytosis and antigen processing of pathogens up-regulates MHC class II & costimulators, changing the surface of the dendritic cell
- causes DC to migrate out of tissue --> the draining lymph node
- a molecule (frequently synthetic) that upregulates costimulators & TLRs on APCs to give primary response a boost
- necessary because many harmless molecules do not produce an immune response
Events in T cell Activation
- 1. CD4 moves closer to TCR & pulls with it kinases
- 2. activated Zap-70 sends a message & activates 3 different sets of pathways
- 3. transcription factors are activated --> move into nucleus and transcribe genes (occurs within ~72 hours after initial activation)
Which (3) key genes are transcribed during T cell activation?
- 1. cytokine genes (*IL-2)
- 2. cytokine RECEPTOR genes (IL-2Rα chain)
- 3. homing molecule gene expression is changed (cell surface molecules that influence where cells moves in body)
What occurs as a result of the change in expression of homing molecule genes?
activated T cells leave the lymph node and move into tissues, generally at the site where pathogen was first encountered
- T cell growth factor
- the binding of IL-2 to its high-affinity receptor (IL-2R) expressed on activated T cells results in huge proliferation & clonal expansion of antigen-specific T cells
What does the costimulator pair B7 --- CD28 function to do?
- it stabilizes IL-2 mRNA
- in the absence of this signal, IL-2 mRNA is rapidly degraded
- (B7 on the APC/DC, CD28 on the T cell)
Cyclosporine A is fungal metabolite used to prevent graft/transplantation rejection. How does it accomplish this?
- it complexes with calcineurin, INHIBITING T cell activation & preventing cytokine synthesis that activates effector cells to reject the foreign tissue
- calcineurin: phosphatase that ACTIVATES T cells
Effector T cell
- cell that is now ready to exert its function
- the change in honing & adhesion molecules on the surface of the cells as a result of gene rearrangement transforms a naive T cell --> effector T cell
CD4+ T cells
- which synthesize and secrete a vast array of cytokines
- act as helper cells for B cell antibody synthesis, & CD8+ T cells, which directly kill cells
cytokines are pleiotropic
- one cytokine can act on many different cells
- many different cell types can make the same cytokine
What are 3 different ways cytokines can exert their effects?
- 1. autocrine = affects the same cell
- 2. paracrine = affects nearby cells
- 3. endocrine = secreted into the circulation
Interleukin 4 (IL-4)
- TH2 cytokine that induces B cells to syntheze IgE
- synthesized by CD4+ T cells (TH2), mast cells, & others
- (anti-IL-4 agents used to treat some forms of asthma)
- TH2 cytokine that activates eosinophils
- anti-IL-5 agents used to treat some forms of asthma
- signature TH1 (a CD4+ T cell subset) cytokine that activates NK cells & macrophages to participate in cell-mediated immunity & kill infected cells of the body
- also induces B cells to switch to synthesizing antibody isotypes that activate complement (key effector pathway in the response to many types of bacteria)
Tumor necrosis factor-α (TNFα)
- activates cells in the inflammatory response
- synthesized by macrophages and NK cells
- (anti-TNFα agents are used to combat rheumatoid arthritis)
What are the 4 major subsets of cytokine-synthesizing CD4+ T Cells?
- TH1: IFNγ, IL-2
- TH2: IL-4, 5, 13
- TH17: IL-17, 22
- Treg: TGF-β, IL-10
What cytokines and effects does the CD4+ T cell subset TH1 have during an immune response?
- cytokines: IFNγ, IL-2
- act on macrophages, NK cells, CD8+ T cells, B cells to make IgG3
- cell mediated immunity
- killing of virus/bacterially infected host cells
What cytokines and effects does the CD4+ T cell subset TH2 have during an immune response?
- cytokines: IL-4, 5, 13
- act on eosinophils, B cells to make IgE & IgG4
- respond to WORMS & allergens
What cytokines and effects does the CD4+ T cell subset TH17 have during an immune response?
- cytokines: IL-17, 22
- act on neutrophils, epithelial cells (especially at mucosa)
- are pro-inflammatory & respond to fungi/extracellular bacteria
What cytokines and effects does the CD4+ T cell subset Treg have during an immune response?
- cytokines: TGF-β, IL-10
- act on other lymphocytes to INHIBIT the function of other sets of T & non-T cells
- (Treg cells themselves express CD25)
Where do the cytokines that drive the differentiation of naïve CD4+ T cell into a particular subset (TH1, TH2, TH17, or Treg) come from?
- cells of the innate immune system, particularly dendritic cells
- innate immune system cells shape the adaptive immune response
- IL-12 --> TH1 cell development
- IL-4 (source unclear) --> TH2 cell development
cytokines synthesized by one CD4+ T cell subset inhibit the development or function of other subsets
- this results is a skewed pattern of the CD4+ T cell responses
- IFNγ & IL-2 made by TH1 INHIBIT TH2's from making IL-4, 5 & 13
- (the reverse applies as well)
Helper T cells (follicular T helper cell, Tfh)
- CD4+ T cells that interact with B cells to induce antibody synthesis
- occurs in secondary lymph node germinal centers
- CD4+ T cells are required for most B cells to synthesize antibody in response to a TD-antigen
- how in response to a TD antigen the cooperating Helper T & B cell may respond to different parts (epitopes) of a single antigen peptide, but the epitopes are part of the same protein
- this linked recognition occurs in the germinal center of secondary lymphoid organs (eg. lymph nodes)
TD-antigen B cell activation
- 1. BCR (B cell receptor = antibody) binds to antigen
- 2. antibody/antigen complex is taken up by cell
- 3. antigen is broken down in acid compartments to smaller peptides
- 4. specific antigen peptides bind to MHC class II
- 5. peptide-MHC class II complexes are trafficked to the cell surface
- 6. here it interacts with a CD4+ T cell that has the matching TCR for the antigen peptide (1st signal…)
- 7. CD4+ T cell CD40L binds to B cell CD40 (2nd signal) -->
- B cell makes antibody & T cell is activated to proliferate cytokines
What two CD4+ T cell derived cytokines induce class-switch recombination?
- TH2 made IL-4
- TH1 made IFN-γ
What defects can cause hyper-IgM syndrome?
- 1. nonfunctional CD154 (CD40L) in boys, X- linked hyper-IgM syndrome
- 2. defective CD40
- 3. defective AID (enzyme required for class switch recombination)
- *any defect in CSR --> hyper IgM syndrome
thymus independent (TI) antigens
- important antigens don't require helper T cells to make antibody
- these include polysaccharides/lipopolysaccharide components of bacterial cell walls
- responses to TI antigens don't normally produce T cell-derived cytokines, B cells do not undergo Ig class switch
- only IgM is synthesized
- IgM is not expressed on B memory cells, memory B cells DO NOT develop from TI antigens
What are two bacteria that produce TI (thymus independent) antigens & therefore create no memory B cells after infection?
- 1. Hemophilus influenzae
- 2. Streptococcus pneumonia
- purified capsular polysaccharide from the bacterium conjugated to a protein --> generate T cell epitopes
- allow bacterial components that usually make TI antigens to be recognized by appropriate TCRs, generating a thymus DEPENDENT immune responses in which B cell class switching occurs & memory develops
CD8+ T cells
- kill host cells that have been infected by pathogens, particularly viruses
- commonly referred to as cytotoxic T lymphocytes (CTL) or killer T cells
- play a role in transplantation rejection and the destruction of tumor cells
- CD8+ T cells that have emerged from the thymus and been activated
- occurs via the same two-signal paradigm
- #1 peptide/MHC class I interact w/ TCR
- #2 costimulator signals
What is required in the responses to most viruses (eg. HIV)?
activation of virus-specific CD4+ T cells is required for the activation of virus-specific CD8+ T cells
What two new events occur upon CD8+ T cell activation?
- 1. formation of granules that contain cytotoxic proteins
- 2. expression of the cell surface molecule Fas ligand (FasL or CD95)
CD8+ T cells Kill via Two Pathways
- 1. contents of granules in activated CD8+ T cell pass into the target cell --> activate apoptotic mechanisms --> cell death
- 2. interaction of Fas Ligand (CD95) on the CD8+ T cell with Fas on the target cell --> apoptoses the target cell
What are the major granule constituents involved in CD8+ T cell target-cell killing?
- perforin: molecule that polymerizes to form ring-like transmembrane pore in target-cell membrane
- granzymes: pass into target cell through perforin made pores & interact with intracellular components to induce apoptosis
What is a signal that TERMINATE CD8+ T cell activation?
- 1. induction of CTLA-4 (CD152) on activated T cell surface
- CTLA-4 (CD152) competes with CD28 to bind to B7 on APC surface
- unlike the CD28-B7 interaction, B7-CTLA-4 transmits a negative signal to the activated T cell, turning off the response
- [CTLA-4 (CD152) can be used in therapies, such as melanoma, to dampen T cell response]
a lymphocyte – a CD4+ or CD8+ T cell or a B cell – that has been stimulated by antigen (in a primary response) and that is activated in a second or subsequent response by the same antigen
Thymus Dependent (TD) Antigen
an antigen that requires T helper cells to cooperate with B cells to synthesize antibodies
Thymus Independent (TI) Antigen
an antigen that does not require T helper cells for B cells to synthesize antibodies
Which antigens trigger which responses?
- • Infectious pathogens (TD) – eg. viruses and bacteria
- CD4+ T cells, CD8+ T cells, antibody (IgM, IgG, IgA or IgE) & γδ T cells (especially mycobacteria)
- • “Harmless” TD antigens – eg. vaccine protein
- CD4+ T cells & antibody (IgM, IgG, IgA or IgE)
- • Worms and allergens
- CD4+ TH2 cells & IgE antibody
- • TI antigens – eg. bacterial polysaccharide
- • Tumors
- if immune response is made, predominantly CD8+ T cells (NK, if no MHC class I expression)
- therapies = enhance immune response (by injecting tumor antigens expressed on DC (prostate cancer), or inhibiting turn off signals)
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