Lec9 Effector Mechanisms Flashcards
Functional roles of CD4 and CD8 Cells
CD4 helper cells secrete cytokines
- allow other cells of immune system to develop functional response
CD8 CTLs lyse cells
- destroy infected cells, limit spread infection, cause of autoimmune disease, transplant rejection, tumor destruction
TH1 T cell activity
- macrophage activation [by release IFN-gamma and binding CD40L to CD40 on macro surface]
- help cytotoxic T cells proliferate
- complement-fixing antibodies
- against intracellular microbes
- role in autoimmune disease, tissue damage associated with chronic infection
TH2 T cell activity
- anti-parasitic [holminthic] response
- allergic response
- IgE production
- mast cell, eosinophil activation
- alternate macrophage activation
- secretes IL-4, IL5, IL-13, IL-10
TH17 T cell activity
inflammatory response
- release IL-17: cause inflammation, neutrophil response and anti-microbial peptides
- release IL-22: cause increased barrier function and anti-microbial response
- against extracellular bacteria, fungi
- can lead to organ-specific autoimmunity
T reg cell activity
suppress immune response
What is IFN-gamma? What does it do?
- cytokine released from TH1 cells
- secretion from TH1 is induced by IL-12 from macrophages
Function
- increases expression of MHC and B7 on pAPC so induce activation of more T cells
- enhances ability of macrophage to kill pathogen
- helps B cells produce complement binding and opsonizing IgG antibodies [promotes opsonization and thus phagocytosis by macrophages]
What will naive T cell differentiate into in presence of IL-2?
TH1 cells
What does a macrophage do once it is activated by T TH1 cell?
- produces ROS, NO, lysosomal enzymes: kill microbes in phagolysosomes
- secretes cytokines [TNF, IL-1, IL-12] and chemokines: recruit leukocytes [inflammation]
- increases expression MHC molec and costimulators: amplification T cell response, increase T cell activation
What causes naive T cell to differentiate into TH2?
presence of IL-4, source not clear
What is IL-4?
- Cytokine that causes naive T differentiation to TH2, source not clear
- then secreted by TH2 to activate B cells for antibody/IgE production
- along wtih IL-13 also increases mucus secretion and peristalsis in GI, and activate macrophages
What is IL-5?
Cytokine secreted by TH2, causes eosinophil activation and release of toxic granules
Balance between TH1 and TH2
If start to develop TH1 response, it inhibits TH2 response and vice versa
Response to Lieshmania major
- usually by TH1 get recovery
- BALB/c mice get response by TH2 leading to disseminated infection
Response to mycobacterium leprae
- some patients TH1 response, get tuberculoid leprosy
- some patients have defective TH2, get lepromatous leprosy
3 signature transcription factors for differentiation naive T Cell
T-bet –> TH1
GATA-3 –> TH2
RORyT –> TH17
Two mechanisms of CTL differentiation and proliferation
- CD4 T cell produces cytokines that stimulate CTL differentiation [actual differentiation requires presence of CD4, cytokines come from the CD4]
- CD4 T cell enhances the ability of APC to stimulate CTL differentiation [actual differentiation part does not require presence of CD4, cytokines come from the pAPC]
If you have an efficient enough antigen presenting cell, can activate without costimulation of CD4
Cytotoxic T Lymphocytes
- mature activate CTl recognizes target cell that expresses MHC class I without costimulation
- CTL delivers kiss of death = granules of perforin and serine esterases
- CTL detaches and can go on to kill other cells
- target cell undergoes apoptosis, takes time
TAP
When virus infects cell, viral protein made and some goes through proteasome and broken down, goes through TAP and binds MHC-I in ER inducing MHC1 to be transported to surface
What is CTLA-4?
on T reg cells, binds B7 on APC and delivers negative signal to arrest T cell activation
What is IL-10?
- an inhibitory cytokine produced by some T-regs
- inhibits expression co-stimulatory molecules and class II MHC on pAPC
- also enhances b cell survival and proliferation and antibody production
What is TGF B?
cytokine that suppresses T cell response
?
Once you are exposed to antigen, T cell induced wtih somatic mutations
Properties of antibodies
- released in lymph nodes, bone marrow
- function distal to point of release
- use Fab [fraction antigen binding] portion to bind
- Fc region dictates function
- Produced during first exposure, larger amounts with additional exposure
- isotype switching, affinity maturation, memory
4 Functions of antibodies
- neutralize microbes and toxins
- bind microbes/antigens and act as opsonin [facilitate phagocytosis]
- antibody-dependent cellular toxicity: NK cells have Fc receptors, bind antibody and kill cells
- activate complement pathway: leads to lysis microbes, phagocytosis/opsonization, inflammation
What is neutralization by antibodies? Which antibodies do this?
Antibody block ability of microbe to bind its receptor
- – prevents microbe infecting cell
- – prevents infected cell from binding and infecting adjacent cell
- – prevents toxin binding cell receptor
All antibodies can do this
Antibody as Opsonin – which antibodies do this?
Only IgG acts as opsonin
- IgG binds microbe
- Complex binds to Fc receptor on phagocyte surface and activates phagocyte
- Phagocytosis and killing of microbe
What is antibody dependent cellular cytoxicity [ADCC]? Which antibodies do this?
Only IgE or IgG
IgE: binds helminth, eosinophil binds IgE by high affinity FcR receptor, releases cytotoxic stuff that kills helminth
IgG: binds infected cell, NK cell binds IgG by low affinity FcR receptor, kills cell
Difference in IgE vs IgG ADCC?
IgE: reacts to helminth, uses high affinity FcR on eosinophil
IgG: reacts to infected cell, uses low affinity FcR on NK cell
Which antibodies initiate complement pathway?
IgG and IgM antibodies via classical pathway
3 Major functions of complement pathway
- opsonization
- cytolysis
- inflammation
Function of IgM
- largest antibody, held together by J chain
- first antibody produced, on surface of all naive B cells
- activates complement
Function of IgG
- most important and universal
- activates complement
- can pass through placenta
- binds Fc -gamma receptors on phagocytes
- always monomer
Function of IgA
- monomer in blood stream or dimer in mucosal sites
- connected by J chain [like IgM]
- blocking antibody = blocks binding
- doesn’t activate complement or act as opsonin
- wrapped in secretory piece
- primarily in secretions
- protects against infections of mucous membranes
Transport of IgA through epithelium
- produced by plasma cells in mucosa of GI and respiratory tracts
- binds poly-Ig receptor on epithelial cell and gets endocytosed into cell
- when gets to luminal side of epithelial cell, IgA cleaved but keeps Poly-Ig receptor that becomes wrapped around it [secretory piece]
What is the secretory piece in IgA?
- the part that wraps around the IgA
- made of leftover from Poly-Ig receptor of epithelial cell
- protects IgA from environment
Function of IgD
- monomer
- only found on B cell surface, not secreted
- no effector function
Function of IgE
- 5 domain structure
- binds mast cell Fc receptor
- function in allergy and immunity to parasites/helminths
- when you are exposed to allergen the second time, serves as receptor on surface of B cell causing them to release vasoactive substances
