Lectures 6-9 Flashcards
B cell receptors & antibodies “BCR & Abs”
-directly recognize antigens
-can recognize diverse antigens - proteins, carbohydrates, lipids, nucleic acids
T cell receptors “TCR”
-can only recognize antigens presented in the context of MHC “major histocompatibility complexes” molecules
-only recognize peptide antigens
(TCR) Heterodimer
Two different chains embedded in T cell membrane that recognize antigens
-alpha + beta chains (95%)
-gamma + delta chains (5%); May recognize carbohydrate antigens
(TCR) Accessory Molecules
-closely associated w/ TCR
-needed for signal transduction
-CD4 (T helper) & CD8 (T cytotoxic)
-CD3 complex (6 peptide chains that transduce signals)
-LFA1 (CD11) = integrin that docks T cell to APC
(TCR Diversity) Gene rearrangement / somatic recombination
-during T cell development
-recombinase enzyme: coded by “RAG proteins” = Recombination Activating Genes (RAG 1 & 2) on chromosome 11
-NO somatic hypermutation
-NO class switching
ITAMS
Immunoreceptor tyrosine-based activating motifs
-activated by phosphorylation
-accessory proteins
-essential for signal transduction
“MHC” Major Histocompatibility Complex
-determinant of tissue compatibility / graft rejection
-self vs non-self
-enables immune system to recognize cells infected w/ Intracellular microbes and cancer cells
-MHC recognizes protein antigens only
-MHC is needed for T cells to recognize antigens
MHC I
-found on all nucleated cells
-present endogenous (Intracellular) peptides; includes self proteins and viral/bacterial proteins
-heterodimer = alpha + B2 macroglubulin assists w/ folding
-peptide groove in the alpha chain
-presents peptides of 8-11 amino acids
-t cytotoxic (CD8 activation)
MHC II
-found on B cells, macrophages, dendritic cells = APCs
-heterodimer = alpha & beta chains but both insert into the cell membrane
-peptide groove between alpha & beta chains
-presents peptides of 30+ amino acids
-T helper (CD4 activation)
MHC restriction
-T cells are specific for both antigen & MHC molecule
-The T cell can only react w/ its specific antigen if it is presented by a self MHC molecule
-TCR interaction with self MHC is learned in the thymus during development
Cell Mediated Immunity
-TCRs only recognize processed antigens
-Antigens must be presented by an MHC molecule on the surface of an APC
MHC I are found on nearly all cells
MHC II are found on B cells, macrophages, and dendritic cells (professionals)
MHC Selectivity (CD4+ = T helper)
-Recognize antigens presented in the context of MHC II
-MHC II is found on APCs (B cells, macrophages, Dendritic cells
-Presents exogenous peptides = extracellular
Role: produce cytokines to tell other immune cells what to do (humoral & cellular responses)
HMC Selectivity (CD8+ = T cytotoxic)
-Recognize antigens presented in the context of MHC I
-MHC is found in all nucleated cells
-Presents endogenous peptides = Intracellular
Role: kill cells with the MHC I - Antigen complex
Antigen Processing
-cleaving the proteins into smaller peptides which are the correct size for MHC I or MHC II molecules
- takes minutes - hours
-peptide fragments combine with the MHC molecules inside the cell
-MHC-peptide complex travels to the cell surface where it displays peptide fragments to T cells
Antigen Processing: MHC I
-Ubiquitin-tagged protein is processed by proteosome in the cytosol
-TAP proteins transport the peptides into the ER
-MHC I + peptide assembled in the ER
-MHC I - peptide transported to cell surface
-MHC I - peptide recognized by CD8 = T cytotoxic (kills cells)
Antigen processing: HMC II
MHC II + invariant leaves ER in vesicle
-phagolysosome cleaves protein into smaller peptides
-MHC II + peptide assembled in vesicle
Recognition & binding
-PRRs recognize PAMPS
Ingestion / Internalization
-receptor mediated endocytosis
-macropinocytosis (dendritic cells)
Destruction
-by lysosomal components within vesicles = phogolysosome
(Acid hydrolases, Reactive oxygen species ROS, Nitrous oxide (NO))
Antigen processing: MHC II Ag processing & presentation
MHC II + invariant chain leaves ER in vesicle
MHC II + peptide assembled in vesicle
MHC II - peptide transported to cell surface
MHC II - peptide recognized by CD4+ = T helper
Secretion of Cytokines & Chemokines
Attracts & stimulates other cells of immune system
IL1
Increases permeability of vascular endothelium; stimulates IL6 production
IL6
Acts on the liver to produce acute phase proteins: Inflammation
IL8
Attracts & activates neutrophils; increases permeability of vascular endothelial
IL12
Activates NK cells; influences lymphocyte differentiation
Assembly with MHC I or MHC II is determined by the route through the cell
Only peptides (= protein) are presented by MHC
TCR
-95% alpha + beta chains
-5% gamma + delta chains MAY recognize carbohydrates
Superantigens
-activate large numbers of T cells without attaching to the groove of MHC molecules
-non specific attachment & activation: binds beta subunit of MHC
TCR binds
MHC-peptide
Co-stimulation
CD4/CD8 binds MHC II/I respectively
Lck = tyrosine kinase associated with the tails of CD4/CD8 mediate the phosphorylation of ITAMs
CD11 (LFA1) - binds CD54 (ICAM 1 on APC)
CD28 - binds B7 (on APC)
Signal Transduction
CD3 complex = 6 peptide chains
Clonal Expansion
Activated T cell undergoes numerous mitotic divisions
Differentiation
CD4 = T helper
CD8 = T cytotoxic
Memory
Response
-T cell migrates to site of infection
-Production of cytokines
In humoral immunity
-naive B cells leave bone marrow -> circulation -> secondary lymphoid organs
-important against non-protein antigens
T-cells
Only recognize processed peptide antigens presented by MHC
B-cells
Recognize naive/unaltered conformational antigens
-non-protein (thymus independent antigens)
-protein (thymus dependent antigens)
Thymus independent = “T independent” (TI)
-T cells are not needed
-Non protein antigens
-Induce clonal expansion & differentiation by BCR signaling alone
-multivalent antigens cross-link many BCRs, signal for activation & proliferation, differentiation into plasma
-only IgM produced (small amounts of IgG)
-no isotype switching (needs CD40-CD40L interaction with T helper)
Thymus dependent = “T dependent” (TD)
-T helper cells are required
-Protein antigens
-BCR clonal expansion & differentiation requires additional signal from T helper
-Induce GC responses
-Isotype switching
Most pathogens contains both TI & TD antigens
T-independent B cell activation: Initiation
Antigens (polysaccharide, lipid, nucleic acid)binds more BCRs
T-independent B cell activation: co-stimulation
-CD21 (CR2) - binds C3d
-CD81
-CD19
T-independent B cell activation: signal transduction - ITAMs
-clustering of bound receptors -> phosphorylation of ITAMs
-clonal expansion
-some memory B cells
-little / no isotype switching - IgM produced mainly
-little / no affinity maturation
T-dependent B cell activation: B cells are APCs Initiation
BCR - binds antigens; Receptor - mediated endocytosis; MHC II - peptide
B cell presents MHC II - peptide to T helper -> T helper activation
MHC II - peptide - binds TCR
CD40
CD40 - binds CD40L (on T helper)
-promotes B cell activation
-promotes isotype switching
-promotes other APC function
CD40L deficiency “hyper IgM syndrome” - because no class switching is taking place
B7
Binds CD28 (on T helper) - T helper cytokines
IL4
-B cell proliferation (+IL2)
-IL4 alone switch to IgE
-IL4 + IFN gamma switch to IgG
IL5
-B cell differentiation into plasma cells
-IL5 + TGF, BAFF switch to IgA
-Activates eosinophils
IL6
-B cell differentiation into plasma cells
Isotype switching
-requires cytokine signal to form T helper (& CD40-CD40L)
-constant portion of heavy chain changes; effector end changes
-variable region stays the same; specificity is the same
Affinity maturation
-occurs in GOs
-it is the result of somatic hypermutation followed by positive selection of high affinity B cells
-high affinity B cells give rise to long-lived plasma cells & memory B cells
The primary Ab response
Generates memory B cells
The secondary Ab response
-rapid recognition & Ab synthesis - memory B cells
-rapid isotype switching from IgM-IgG
-Stronger response - more IgG & higher affinity
Memory B cells
-do not secrete Abs
-typically isotype switched
-typically higher affinity
-long lived
Maternal IgG is transported by the neonatal Fc receptor
-across the placenta to the fetus
-across the gut epithelium to the neonate (colostrum)
-human milk contains IgA
Passive immunity (natural)
-(3-4) month protection
-protection is as good as the titer of IgG in the mother against the specific organism
IgM
First Ab produced
IgA
Found in secretions
IgD
BCR
IgG
Most prevalent, crosses placenta
IgE
Allergic reactions, multicellular parasites
Agglutination
Clumping of particles: IgM, IgG, IgA
Opsonization
Opsonins to tag foreign pathogens for phagocytic elimination ; IgG
Neutralization
IgM, IgG, IgA
Complement activation
IgM, IgG
Which is false regarding MHC I?
Recognized by CD4 helper T cells
What is false about Superantigens?
Superantigens activate T cells by attaching to the groove of MHC molecules
What type of antigens can induce germinal center responses?
T-dependent antigens
What is the role of CD40 in B cell activation?
Isotype switching, the constant portion of the heavy chain changes
T cell precursors are produced in the
Bone marrow
T cells develop & mature in the
Thymus
T lymphocytes (T helper)
T helper = CD4+
-monitor the body for extracellular microbial infections
-activate/stimulate other cells of the immune system
T lymphocytes (T cytotoxic)
T cytotoxic = CD8+
-destroy host cells infected with Intracellular pathogens
-destroy tumor cells
IL-2
T cell growth factor
-autocrine (effects the same cell that secreted it)
-paracrine (effects other cells)
Th cells have IL-2 receptors
They differentiate: influenced by cytokines
T helper lymphocytes (CD4) effector subsets
TH1
TH2
TH17
TFH
TREG
T helper CD4+: Th1
Th1 = Intracellular infections (bacteria, virus, protozoa) cell mediated
Differentiation of Th1
Influenced by
IL-12 (from APCs)
IFN gamma (from NK cells & Th)
Th1 secretes:
IFN gamma
TNF
IL-10
IL-13
IFN gamma
Potent activator of macrophages, stimulates activated B cells & IgG production, stimulates Th differentiation, stimulates primed T cytotoxic to become effector cells
TNF
Activated vascular endothelium to express adhesion molecules to recruit leukocytes
IL-10
Reduce macrophage activation
IL-13
Reduces macrophage activation, induces production of mucus in the intestine, increases peristalsis
T helper CD4+: Th2
Parasites & allergies
Secretes:
IL-4
IL-5
IL-10
IL-13
Th2 differentiation is influenced by
IL-4 (from mast cells)
IL-4
IL-4 = stimulates primed B cell proliferation, class switching to IgE, reduce macrophage activation
IL-5
Stimulates B cel differentiation into plasma cells, activates eosinophils & mast cells, class switching to IgA
T helper CD4+: Th17
Fungal & extracellular bacteria
Th17 differentiation is influenced by
IL-6
TGF beta
TH17 secretes:
IL-17 = recruit neutrophils
IL-22 = stimulates epithelial cells to produce anti-microbial peptides to resist microbial invasion
