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)