Antigen Capture and Presentation to Lymphocytes
Adaptive immunity is initiated by recognition of antigens by receptors of
lymphocytes B and T lymphocytes recognize specific antigens
o B (membrane-bound antibodies) --> macromolecules and small chemicals Immune
responses against microbial cell wall and soluble antigens
o T --> peptide fragments of protein antigens and when the peptides are on host surfaces
bound to MHC molecules
MHC molecule association with antigenic peptides in in cells, so T-cell
immunity must be produced in or taken up by cells
Few naïve lymphocytes are specific for any one antigen
o This fraction must locate and react rapidly to the antigen
Defense against a microbe that enters the bloodstream is dependent on antibodies that bind it,
preventing infection of host cells and help to eliminate it
Producing potent antibodies requires activation of CD4 + helper T cells.
o After it infects the host, the microbe is safe from antibodies, which cannot enter the
cells.
Activation of CD8+ cytotoxic T lymphocytes (CTLs) are needed to kill the
infected cells and eliminate the infection
Helper T cells respond to extra and intracellular microbes that can be internalized into vesicular
compartments in host cells, whereas CTLs kill infected cells that have antigens in the cytosol
and nucleus
MHC molecules play role in segregation of antigen recognition of T cells
Immune system has highly specialized system for capturing and displaying antigens
T lymphocytes recognize peptide antigens bound to MHC molecules of APCs
o MHC is genetic locus whose protein displays immune system molecules
CD4+ and CD+8 T cells see peptides when these peptides are displayed by MHC molecules
o MHC restriction
T cell receptor (TCR) recognizes AA residues and MHC molecules, one peptide displayed by
one of many MHC molecules in every individual
Some T cells presented by nonpolymorphic class 1 MHC-like molecules or without
recruitment for antigen display system
APCs (antigen-presenting cells) capture and display for T-lymphocyte recognition
Naïve T must see antigens presented by dendritic cells to initiate clonal expansion into effector
and memory cells
Differentiated effect cells need to see antigens to activate functions in humoral and cell
mediated.
Capture of Protein Antigens by Antigen-Presenting Cells
Microbe antigens are captured by dendritic and concentrated in peripheral lymphoid organs
o Enter through skin, GI tract, respiratory tract, and genitourinary tract.
o Some enter bloodstream, some produced in infected tissue.
Antigens taken into lymphoid organs: 1. enter lymph or blood and circulate, where they are captures by
dendritic cells and presented to T-cells. Other APCs capture and display to B cells. 2.
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dendritic cells transport antigens to lymphoid organs. Capture antigens, activate dendritic cells,
migrate carrying cells to lymph nodes, and display antigen to T cells.
Interfaces between body and environment are lined by continuous epithelial, which provide
barriers to infection
Dendritic cells: 1. conventional (classical) 2. plasmacytoid
o Majority classical. In the skin, epidermal ones are Langerhans cells.
After activated, lose adhesiveness for epithelial and begin to express
CCR7, which is specific for chemoattracting cytokines produced by
lymphatic endothelium and by stromal cells
Chemokines direct dendritic cells to exit epithelium and migrate through
vessels, draining that epithelium
The process causes dendritic cells to mature into APCs that stimulate T
lymphocytes- causes increased synthesis and stable expression
o Protein antigens of microbes that enter body are transported to and
concentrated in regions of lymph nodes
o Plasmacytoid are named due to resemblance to plasma cells, present in blood and
tissues.
Major source of type 1 interferons in innate immune responses to viral
o Dendritic cells use receptors to bind microbes, which are taken up by phagocytosis or
receptor mediated endocytosis
o While capturing antigens, products stimulate innate immune reactions by binding
TLRs and all other pattern receptor.
Results in production of cytokines such as tumor necrosis factor (TNF)
and interleukin-1 (IL-1)
o Different APC serve functions in T cell-dependent immune responses.
Dendritic cells are inducers of T-dependent responses because these cells are located at
microbe entry and are potent for activating naïve T lymphocytes.
One APC for effector T cells is the macrophage, which is abundant in all tissues
Macrophages phagocytose microbes and display antigens of microbes to
effector T cells, which are reactivated and induce macrophages to kill
these ingested microbes.
B lymphocytes endocytose protein antigens and display to help T cells in lymphoid tissues. Any
nucleated cell containing foreign protein antigens in the cytosol can present peptides
derived from these antigens to CD8+ T cells.
Structure and Function of Major Histocompatibility Complex Molecules
MHC molecules are membrane proteins on APCs that display peptide antigens for recognition by
T-lymphocytes.
MHC, genetic locus, determines acceptance and rejection of tissue grafts
o Individuals who are identical at their MHC locus will accept grafts from each other. MHC
molecules display peptides from microbial protein antigens to T lymphocytes
MHC molecules are proteins encoded by the murine MHC locus in graft rejection
o Proteins were called human leukocyte antigens (HLAs) and are analogous to MHC
in mice.
In vertebrates, MHC contains 2 sets of highly polymorphic genes, called class I and II MHC MHC
contains nonpolymorphic genes, some code for proteins in antigen presentation
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Structure of MHC molecules I and II have extracellular peptide binding cleft
Class 1: alpha chain noncovalently associated with B2-microglobulin that is encoded by a
gene outside the MHC.
o The alpha chain has 3 domains followed by transmembrane and cytoplasmic domains.
Amino-terminal a1 and a2 domains of a chain form 2 walls and peptide binding
cleft that accommodate peptides typically 8-9 AA long.
o The floor of peptide-binding cleft has AA residues that bind peptides for display to
T lymphocytes and the tops of the cleft walls contact T receptor
o Polymorphic residues are in a1 and a2 domains of the alpha chain.
o The alpha 3 domain is invariant and has a site that binds CD8 but not CD4
o CD8+ T cells respond to peptides displayed by class 1, which CD8 coreceptor binds.
Class 2: each has 2 transmembrane chains (alpha and beta), each has two extracellular domains
followed by transmembrane and cytoplasmic.
o Amino terminal of both chains (a1 and B1) contains polymorphic residues and form clef
large enough for peptides 10-30 residues.
o Nonpolymorphic a2 and B2 contain binding site for CD4 T
cell CD4 bind class 2 but not 1.
MHC genes are polymorphic with many different alleles
o 1 individual inherits and expresses only 2 alleles (1/ parent)
MHC genes are codominant, meaning alleles inherited from both parents are equal
o Codominant expression maximizes the HLA proteins expressed by each individual
and enables display of many peptides.
o Class 1 are expressed on all nucleated cells, but class 2 are on dendritic cells,
macrophages, and B-lymphocytes. Class 2 can be thymic epithelial cells and
endothelial cells and be induced on other cell types of cytokine interferon-y.
Three polymorphic class I genes (HLA-A, HLA-B, HLA-C) exist and can express 6
Class 2, every individual inherits each parent 2 separate genes for a-chain and b-chain of HLA-
DP, two encoding DQa and DQb, one or two for DRB, and sometimes HLA-DRB3, HLA-DR4
or HLA-DR5 and one for Dralpha
o Polymorphism in B chains and exclusively in alpha chain for class 1 genes
Set of MHC genes on each chromosome is called an MHC haplotype
o The genes are tightly linked and inherited Mendelian.
Clefts of MHC molecules bind peptides derived from antigens and display these for T cells.
o There are pockets in the floors, where AA fit and anchor the peptides in the cleft-->
anchor residues.
o Each MHC can present only 1 peptide at a time because there is one binding cleft. MHC
restricted CD4+ T and CD8+ can recognize and respond to antigens. (microbes)
MHC molecules display peptides from antigens inside host cells.
Class 1 acquire peptides from cytosolic proteins and class 2 from intracellular vesicles.
Peptide-loaded MHC molecules are expressed on cell surfaces.
o MHC must assemble both chains and bound peptides to achieve stability.
o Empty molecules are degraded inside cells.
o Once peptides bind, they stay for a long time.
MHC can display peptides from individual’s proteins and peptides from foreign protein. New
MHC molecules are constantly being synthesized, ready to accept peptides and
adapt at capturing any peptides that are present.
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During viral infection, host protein synthesis is suppressed, and viral proteins dominate. T cells
specific for self-antigens are killed or inactivated, so T cells are always patrolling.
Processing and Presentation of Protein Antigens
Proteins in a nucleated cell are processed and called proteosomes displayed by class 1, whereas
extracellular are internalized by APCs and processed in late endosomes and lysosomes to be
displayed be class 2.
Segregation ensures T lymphocytes recognize antigens.
Processing of Cytosolic Antigens for Display by Class 1
o Tagging of antigens in the cytosol or nucleus for proteolysis, transport into ER, binding
to new class 1, and transport to cell surface
Proteolysis of Cytosolic Proteins
o Peptides bind class 1 are derived from cytosolic proteins following digestion
by ubiquitin-proteasome pathway.
o Antigenic proteins produced in cytoplasm from viruses in infected cells, from
phagocytosed microbes that may leak, and from mutated host genes.
All are targeted for proteolytic digestion- enabling to be read by class 1.
Binding of peptides to class 1
o Peptides must be transported into ER (peptides from cytosol, MHC from ER)- done
by TAP located in ER membrane.
It binds proteosome generated peptides on the cytosolic side of ER, then pumps
into interior of ER.
New class 1 associate with bridging protein, tapasin that links TAP to
ER membrane
Transport of Peptide-MHC complexes to cell surface
o Peptide loading stabilizes class 1, exported to cell surface.
o Once class 1 binds tightly to one of the peptides generated from proteasomal digestion and
delivered into ER by TAP, it becomes stable and is delivered to surface.
o If MHC does not have peptide to bind, empty molecule is unstable and degraded in ER.
o Class 1 recognized by CD8+ T cells.
o By inhibiting class 1 pathway, viruses reduce presentation of their own antigens to
CD8+ T cells and can evade the of adaptive immune system/
Processing of internalized Antigens for Display by Class 2
o Internalization and proteolysis of antigens.
Antigens destined for class 2 are internalized from extracellular environment.
Dendritic cells and macrophages ingest microbes by phagocytosis and
endocytosis.
Microbes bind to surface receptors for microbial products or to receptors that
recognize antibodies or products of complement activation attached to
microbes.
B lymphocytes internalize proteins that bind to cell’s antigen receptors.
o Binding of Peptides to Class 2 Molecules
Peptides bind to new class 2 molecules in specialized vesicles.
Class 2 synthesize these MHC molecules in ER.
Each class 2 molecules carry a protein called invariant chain (Li), with class 2
invariant chain peptide that binds to peptide-binding cleft of class 2.
Cleft of new molecules is prevented from accepting peptides in ER.
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Class 2 molecule with its associated li migrates from ER through Golgi stacks
and then traveling directly to plasma membrane and is targeted by cytosolic tail
of invariant chain to acidic vesicles.
o Invariant chain is degraded, leaving only CLIP in the peptide binding cleft.
o Ingested proteins are digested into peptides and vesicles contain class 2 called DM,
whose function is to exchange CLIP in class 2.
Transport of peptide-MHC complexes to cell surface
o Peptide loading stabilizes class 2, which are exported to cell surface.
o Can be recognized CD4+ T cell.
o Class 2 do not find peptides can bind and are degraded by proteases.
Cross-Presentation of Internalized Antigens to CD8+ T cells
o Some dendritic cells are ingested antigens on class 1 MHC to CD8 T lymphocytes
Initial response of naïve CD8+ T cells requires antigens by mature dendritic
cells in lymph nodes through naïve T cells circulate.
Some viruses may not infect dendritic cells and these infected cells may not
travel to lymph or produce signals for T cell activation.
o Classical dendritic cells can ingest cells, microbes, and antigens and transport the
ingested antigens into the cytosol, where they are processed by proteasome.
Antigenic peptides are made and enter ER and bind to class 1, which
display antigens for recognition (cross-presentation)
Once differentiated into CTLs, they kill infected host cells or tumor cells
without the need for dendritic cells other than recognition of antigen.
Physiologic Significance of MHC-Antigen
o Restriction of T cell recognition to MHC peptides ensures that T cells see and respond.
o MHC molecules are cell membrane proteins and peptide loading.
o T lymphocytes can recognize antigens of intracellular microbes, which require T-
cell mediated effector mechanism/
o CTLs kill infected cells and eradicate the infection, mechanism to eliminate cytoplasmic
microbes.
oCTLs kill tumor cells, which produce proteins from mutated genes.
o Specificity of CD4 for class II, the peptides by CD4 and function as helper cells
o T cells help macrophages to destroy ingested microbes, activating an effector mechanism
that eliminates microbes that internalize from extracellular.
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o B lymphocytes ingest protein antigens and processed peptides for recognition by CD4+
helper T cells.
Stimulate production of antibodies, which eliminate extracellular microbes.
o During extracellular life, the virus is fought by antibodies and phagocytes, whose production
or functions are stimulated by helper T cells but once a virus has found a haven in the
cytoplasm of cells, it can be eradicated only be CTL-mediated killing.
Structural constraints account for immunodominance from complex protein antigens and for
inability to respond to antigens.
Any protein is proteolytically degraded in APCs, many may be generated but only peptides able to
bind to MHC molecules in that individual can be presented for T cell recognition.
T cells recognize and react against small molecules and even metal ions in an MHC-
restricted manner.
Some chemicals can covalently modify self-peptides or MHC molecules themselves,
creating altered molecules that are foreign.
Some may bind noncovalently to MHC molecules and alter the structure of the peptide-binding
cleft such that NHC complexes are foreign.
Functions of Antigen-Presenting Cells in Addition to Antigen Display
Antigen-presenting cells have peptides for T cells and T cell activation.
Antigen is needed for signal 1 and for T cells, signal 2 is by APCs reacting to
microbes. Bacteria produce lipopolysaccharide (LPS, endotoxin)
o When captured by APCs, LPS act on the APCs through TLR and stimulates expression
of costimulators and secretion of cytokines.
Act in concert with antigen recognition by T cell to stimulate proliferation of T
cells and their differentiation into effector and memory cells.
Antigen Recognition by B Cells and Other Lymphocytes
B-lymphocytes use membrane bound antibodies for recognizing antigens, which may be on
microbial surfaces or may be in soluble form.
Secreted antibodies enter circulation and mucosal fluids and bind to antigens leading to
neutralization and elimination
Macrophages in lymphatic sinuses and dendritic cells adjacent to follicles may capture antigens that
enter lymph nodes and present in antigens, intact form, to B lymphocytes.
B-cell lymphoid follicles of lymph nodes and spleen have follicular dendritic cells, whose
display antigens to activated B cells
o FDCs: not bone-marrow derived, they express receptors that bind antigens with
antibodies or complement by products (C3b and C3d)
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