Immuno Exam 1 - Adaptive Immunity - Intracellular Pathogens Flashcards
Immune response to intracellular pathogens:
What cells are most involved and what do they do?
Different classes of lymphocytes recognize distinct types of antigens & differentiate into effector cells whose function is to eliminate the antigens
B lymphocytes recognize soluble or cell surface antigens & differentiate into antibody- secreting cells → neutralization of microbe, phagocytosis, complement activation
Helper T cells recognize antigens on APC surfaces & secrete cytokines which stimulate different mechanisms of immunity (→ activation of macrophages, T & B lymphocytes) & inflammation
Cytolytic T cells (CTL) (CD8+) recognize antigens on self infected cells and kill these cells
NK cells recognize changes on the surface of infected cells and target & kill these cells
Describe the role of NK cells in intra immune response
NK cells recognize changes on the surface of infected cells and target & kill these cells
Natural Killer cells are activated when inhibitory receptor is not engaged
Virus inhibits MHCI expression → lack of engagement of inhibitory receptor → activated
Activation leads to degranulation, degranulation kills the infected cell
*normally, both receptors (activator & inhibitor) are engaged, so NK cell won’t respond
NK cells kill host cells infected by intracellular microbes, eliminating reservoirs of infection
Respond to IL-12 produced by macrophages & secrete IFN-γ which activates macrophages
Describe the role of CD4 Th1 cells in the adaptive immune system
Effector CD4+ TH1 cells subset recognize the antigens of microbes ingested by phagocytes → cytokine release → activation of phagocytes to kill microbes & induce inflammation
Describe the role of CD8 lymphocytes in the adaptive immune response
CD8+ lymphocytes also produce cytokines that elicit the same reactions, but recognize & kill microbial antigens in the cytoplasm of infected cells
Describe Migration of effector T cells and other Leukocytes to the site of infection
Migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues
Antigen recognition in lymph nodes → T cell expansion & differentiation → enter circulation → migration to site of antigen → effector T cells encounter antigens in peripheral tissues → activation
What are the 2 steps required for T-cell activation?
Naïve T cells come into contact with APC in lymph nodes
Interactions with APC are necessary to activate the T cells
1. TCR recognition & engagement of MHC peptide; MHC on APC
2. Co-stimulatory molecule binding; CD28-B7 interaction
Describe the migration of naive T cells
Naïve T lymphocytes home to lymph nodes as a result of L-selectin binding to its ligand on high endothelial venules which are present only in lymph nodes
Describe how effector T cells are retained in the periphery
Migrate to site of infection by using receptors to bind to ligands that are induced on endothelium by cytokines produced during innate immune reactions to microbes
T cells that recognize microbial antigens in extravascular tissues are retained at these sites by integrin-mediated adhesion to the extracellular matrix
Are all T cells retained in the target tissue?
NO! These antigen specific T cells perform their effector function of eradicating the infection, whereas T cells that do not see antigen return via lymphatic vessels to circulation
What happens to T cells on endothelium at site of infection?
Increased expression of adhesion molecules on endothelium at site of infection → stable binding of activated T cells → effector T cells enter peripheral tissues → antigen recognition by T cells specific for microbe
Do T helper cells kill in the intracellular immune response?
NO! T cells help macrophages kill, macrophages do the killing
Describe Macrophage activation by T cells
Effector T cells recognize antigens of ingested microbes on macrophages & express CD40L which engages CD40 on the macrophage, the T cells secrete IFN-γ which binds to receptors on the macrophage
This signals activation of macrophages to produce microbial substance that kill ingested microbes & secrete cytokines that induce inflammation (TNF, IL-2, chemokines, IL-12) & active T cells to express more MHC molecules and co stimulators (B7 molecules) which enhance T cell response
Describe cytokine mediated interactions b/t t cells and APCs
Between T lymphocytes, APCs with ingested microbes & macrophages
Macrophages that encounter microbes secrete cytokine IL-12 which stimulates naive CD4+ T cells to differentiate into IFN-γ secreting TH1 cells & enhance IFN-γ production; activates macrophages to kill microbes
What determines the outcome of intracellular infections?
Th1/Th2 activation balance determines the outcome of intracellular infections
Naive CD4+ T cells may differentiate into Th1 cells which activate macrophages via IFN-γ, TNF; or Th2 cells which inhibit macrophage activation via IL-10, IL-4, IL-13 secretion
CD4 & CD8 cooperation in eradication of intracellular infections
In macrophage infected by intracellular bacterium, some bacteria sequestered in vesicles & others may except into cytoplasm
CD4+ recognizes antigens derived from the vesicular microbes & activate the macrophage to kill microbes in the vesicles
CD8+ recognizes antigens derived from cytoplasmic bacteria & are needed to kill the infected cell, eliminating the reservoir of infection
How do CD8 cells become CTLs?
CTL CD8+ kill targets that express the same class 1-associated antigen that triggered the proliferation & differentiation of naïve CD8+ T cells to become CTLs
- MHCI-peptide complex
- Accessory molecules CD8 & LFA-1
Upon conjugate formation, recognition of MHCI-peptide complexes on the target cell induces TCR clustering & generates biochemical signals that activate CD8+ T cells to proliferate & differentiate into CTLs
o MAP kinases (AP-1)
o Protein kinase C (NF-κB)
o Calcineurin (NFAT)
Activated CTL releases granule contents which delivers a lethal hit to the target
What proteins are in lytic granules of cytotoxic T-cells?
Perforin – polymerizes to form pore in target membrane for granzymes & granulysin entry
Granulysin – induces apoptosis
Granzymes – serine proteases which active apoptosis once in the cytoplasm of target
Describe how Granzyme B works
Granzyme B induces apoptosis by activating caspases
Caspase 3 activation will lead to Caspase Activated DNAase (CAD)
CAD casues DNA fragmentation & thus apoptosis
*can also directly activate CAD
By activating BH3-Interacting Domain death agonist (BID)
BID destroys integrity of mitochondrial outer membrane
Pro-apoptotic factors are released from mitochondrial membrane
Cytochrome C will activate caspase 9 & endonuclease G which cleaves DNA
What is the timeline for polarization and release of T-cell granules in minutes?
T0 = T cell recognizes & binds to target cell
T1-4 = granules move toward point of contact
T 40 = release of granules into space between T cell & target (apoptosis has begun)
Describe FasL on CTL CD8) interaction
FasL on CTL (CD8+) interacts with Fas receptor on target cell → apoptosis
Fas receptor trimerizaiton activates the death domain
Fas Associated Death Domain leads to signaling cascades that activate caspase 8
*Caspase 8 can activate BID and caspase 3 also
What is Fas (CD95)?
A member of the TNF family expressed on surface of T cells
Initiates signaling cascade which results in apoptosis
Death pathway is initiated upon binding of Fas to Fas ligand expressed on T cells
Fas-mediated killing is important for maintenance of T cell self-tolerance
Mutations of gene cause systemic autoimmune disease
What is FasL?
Membrane protein of the TNF family expressed on T cells
Bind to Fas to initiate apoptotic cell death of target cell
How does CD4 activate macrophages?
CD4+ produces IFN-γ to activate macrophages
Produce cytokines to provide costimulation for CD8+ T cell activation (→CTLs)
Produce cytokines to enhance activity of APCs (→ CTL differentiation)
What are some ways that intracellular pathogens try to thwart the immune response?
Intracellular pathogens try to thwart the immune response by…
Inhibition of proteasomal activity (EBV, human CMV)
Block in TAP transport (HSV)
Block in MHC synthesis and/or ER retention (adenovirus, human CMV)
Removals of class I from ER (CMV)
Interference with CTL recognition by ‘decoy’ viral MHCI-like molecules (murine CMV)
