Immunology Ch 3 49-69
Antigen Capture and Presentation to Lymphocytes
-Adaptive immune responses initiated by recognition of antigens by antigen receptors of
lymphocytes; B/T cells differ in the types of antigens they recognize
-B cells recognize antigens in soluble form or cell surface form an small chemicals, such as those
of microbial cell walls and soluble antigens
-T cells can only see peptide fragments presented by specialized cells, and so T cell responses
are mediated against intracellular protein antigens
Antigens Recognized by T Lymphocytes – majority of T cells recognize peptide antigens only
when displayed by MHC molecules of antigen-presenting cells, which is called MHC restriction
-TCR can recognize some residues of antigen and some on MHC
-Cells that get microbial antigens and display them for T cells are antigen-presenting cells (APCs)
-Naïve T cells need to see antigens on presented on dendritic cells (most efficient at
presenting antigen to cause immune response
-effector T cells also need to see antigen presented on various APCs
Capture of Protein Antigens by APCs – protein antigens of microbes that enter the body are
captured mainly by dendritic cells and concentrated in peripheral lymphoid organs
-all body connections to external environment are lined with epithelia containing dendritic cells
-two major populations of dendritic cells: (1) conventional, and (2) plasmacytoid
-majority are conventional and in epithelial linings (in the skin, they are called
Langerhans cells)
-Plasmacytoid dendritic cells resemble plasma cells and are present in blood and tissues, and are
the major source of type I interferons in innate immune response against viruses
-Dendritic cells use various receptors, such as lectin receptors (for carbohydrate structures).
-these antigens enter the cell via receptor-mediated endocytosis
-at the same time as ingestion, microbial products are binding to the DC’s TLR receptors to
stimulate innate immune reactions from these cells in addition to macrophages
-results in inflammatory cytokine production (TNF and IL-1) to activate dendritic cells
-Activation of conventional dendritic cells at epithelial barriers causes them to lose adhesiveness
to epithelium and begin to express CCR7 specific for chemokines produced by lymphatic
endothelium and stromal cells in T cell zones of lymph nodes
-these chemokines direct DC’s to exit epithelium and migrate through lymphatic vessels
to lymph nodes
-during this time, the dendritic cells mature from being able to capture antigens to being
able to stimulate T cells by stable expression of MHC molecules displaying antigen and
co-stimulators
-different types of APC serve distinct functions in T cell immune responses
-dendritic cells are principle inducers and are most potent for T cell activation
-macrophages phagocytose microbes and display antigens to effector T cells, which
activate the macrophages to kill the microbes
-B cells ingest protein antigens and display them to helper T cells in lymph tissues,
important for development of humoral response
-All nucleated cells can present antigens derived from microbes in cytoplasm to CD8 T cells
Structure and Function of MHC Molecules – MHC are membrane proteins on APCs that display
antigens for T cell recognition
-individuals who are identical at their MHC locus will accept grafts from one another
-Human MHC proteins are called human leukocyte antigens (HLAs)
-In all species, two classes of MHC genes exist: Class I and class II MHC genes
Structure of MHC Molecules – class I and II MHC are membrane proteins containing peptidebinding cleft at the amino-terminal end
-Class I MHC – α chain associated with a β2-microglobulin endcoded by exogenous gene
-α1 and 2 domains of class I form peptide-binding cleft (for 8-11 amino acids)
-the amino acids that differ among MHC molecules are at the α1 and 2 domains,
some of which participate in variation of floor of peptide-binding cleft
-otherpolymorphisms are on top of cleft to vary T cell recognition
-Class II MHC – consists of 2 chains, an α and a β chain; amino-terminal region, called α1
and β1 contain polymorphic residues to accommodate peptides of 10-30 residues
-nonpolymorphic β2 domain binds T cell coreceptor CD4; CD4+ T cells only bind
MHC class II
Properties of MHC Genes – MHC genes are codominantly expressed; alleles from both parents
expressed equally
-There are 3 different MHC Class I: HLA-A, HLA-B, HLA-C and each has 1 allele per
parent, therefore, 6 MHC Class I variants can be expressed on any cell
-for MHC class II, there is ONE pair of HLA-DP genes (DPA1 and DPB2 for α and β chains,
ONE pair of HLA-DQ genes (DQA1 and DQA2), one HLA-DRα (DRA1) gene from each
parent, and one or two HLA-DRβ gene from each parent (DRB1 and DRB 3, 4, 5)
-polymorphism resides in the β chains
-total amount of MHC class II that can be expressed is considerably more than 6
-set of MHC alleles present on each chromosome is called MHC haplotype, and each
HLA allele is given numeric designation, eg. HLA-A2, B5, DR3
-MHC genes are HIGHLY POLYMORPHIC, lots of alleles in the population
-no two people have the same two genes, and MHC alleles are inherited
-Class I MHC is on all nucleated cells; class II are on dendritic cells, B cells, and macrophages
-Class II molecules expressed on thymic cells and can be induced in others by IFN-g
Peptide Binding to MHC – peptide-binding clefts of MHC bind peptides derived from protein
antigens and display these for recognition by T cells
-pockets in the floors of clefts bind peptide antigens to anchor them
-each MHC can only present one peptide at a time, but each MHC can present different peptides
-MHC molecules bind only peptides and not other types of antigens
-MHC molecules acquire their peptide cargo during biosynthesis, assembly, and transport in cell
-that’s why only intracellular peptides are recognized by T cells
-only peptide-loaded MHC molecules are stably expressed on cell surface
-MHC must assemble both chains and bound peptide to have stable structure, and
empty molecules are degraded within cells
-MHC molecules can display peptides derived from individual’s own proteins as well as foreign
peptides
-quantity of self-proteins more than microbial antigens, suggesting that new MHC
always made to be able to present foreign antigens
-autoimmune T cells are killed in thymus
-MHC molecules are capable of displaying peptides but not full antigens: antigen processing
Processing and Presentation of Protein Antigens – extracellular proteins that are internalized
by specialized APCs are processed in endocytic vesicles and displayed on MHC Class II, whereas
proteins in the cytosol of any nucleated cell are expressed on MHC class I molecule
1. Processing of antigens for Class II MHC – main steps include ingestion of antigen,
proteolysis in endocytic vesicles, and association of peptides with class II MHC
a. Internalization occurs via phagocytosis, receptor-mediated endocytosis, pinocytosis
b. B cells specifically internalize antigens bound to antigen receptor
c. Proteins may fuse with lysosomes to be broken down
d. Class II MHC APCs constantly synthesize MHC molecules in the endoplasmic
reticulum; each new synthesized MHC-II carries an invariant chain I, containing a
sequence called the class II invariant chain peptide (CLIP) that binds tightly to
peptide binding cleft
i. Peptide binding cleft is occupied and prevented from accepting peptides in
ER that are destined to bind MHC class I
e. MHC-II with I chain is targeted to late endosomal vesicles that contain a class II
protein called DM whose function is to exchange CLIP with a higher affinity peptide
that may be available in this compartment
f. Once it binds new peptide, MHC becomes stable and is delivered to cell surface
2. Processing of Cytosolic Antigens for Class I MHC – main steps include generation of
antigens in cytoplasm or nucleus, proteolysis by specialized organelle and transport into ER,
and binding of peptides to newly synthesized class I
a. Antigenic proteins may be produced in cytoplasm from viruses living inside infected
cells, from phagocytosed microbes that leak out, and from mutated genes (tumors)
b. All of these proteins are targeted for destruction by ubiquitin-proteasome pathway;
tagged with ubiquitin and targeted to proteasome
c. Under inflammatory conditions, proteasomes cleave cytosolic and nuclear proteins
into sized that fit with MHC class I molecules
d. MHC synthesized in ER, and many peptides are in the cytosol; this problem is
overcome by transporter associated with antigen processing (TAP) located in ER
membrane, which binds proteasome-generated peptides and pumps them into the
ER to bind to newly synthesized MHC class I molecule
Cross-presentation of internalized antigens to CD8 T cells – dendritic cells are capable of
ingesting virus-infected cells and displaying viral antigens bound to class I MHC molecules to
CD8 T lymphocytes; this is called cross-presentation, where one type of cell (dendritic cell), is
able to present antigen of other, infected cells and prime naïve T cells specific for these antigens
-both CD4 and CD8 T cells may be activated close to one another
Physiological significance of MHC-associated antigen presentation – restriction of T cell
recognition to MHC peptides ensures that T cells see and respond only to cell-associated antigen
-segregating Class I and II pathways of antigen processing makes sure that the immune system is
able to respond to extracellular and intracellular microbes in different ways to best defend
against them
-CD4 lymphocytes specific for class II peptides, which help B cells produce antibodies and help
phagocytes to destroy the microbes
-neither of these mechanisms are effective against viruses
-cytosolic antigens are processed by MHC class I on all nucleated cells and are recognized by CD8
positive lymphocytes which turn into CTL and kill the cell
-structural constraints on peptide binding to different MHC molecules, including length and
anchor residues, account for the immunodominance of some peptides derived from complex
protein antigens and for inability of some individuals to respond to certain protein antigens
-Immunodominant peptides – those peptides out of a whole protein that can bind MHC
Functions of Antigen-Presenting Cells in Addition to Antigen Display – antigen-presenting cells
not only display peptides for recognition by T cells, but in response to microbes, they also
express additional signals for T cell activation, such as a second signal
Antigens recognized by B cells and other lymphocytes – B cells use membrane-bound
antibodies to recognize antigens, including peptides, sugars, lipids, and small chemicals which
cause them to differentiate into plasma cells secreting antibodies
-B cell-rich areas in lymphoid follicles are follicular dendritic cells (FDCs) which display coated
antibodies or by complement such as C3b or C3d
-FDCs use receptors called Fc receptors specific for one end of antibody molecule to bind
antigen-antibody complex