Immunology Flashcards
1
Q
Antigen
Immunogen
Hapten
A
Antigens: A molecule that can induce an antibody response
Immunogen: A molecule that induces an immune response (typically a protein or a large, multivalent non-protein)
Hapten: An antigen (such as a small chemical) that can bind to antibodies but does not induce an immune response on its own
2
Q
Immunogenicity
A
Size, repetition (if not a protein, needs repetition), composition (protein, polysacc, etc.)
3
Q
Comparison of antigens: hapten, polysacc, protein
Binds antibody? Activates B cells? Activates T cells?
A
4
Q
To generate an immune response to a hapten….
A
- •Multiple copies of the hapten can be attached to a protein
- A T cell dependent response can be elicited that will drive production of antibodies specific for the hapten
- The protein is known as a carrier protein
- Immune responses to haptens can be pathogenic (contact hypersensitivity)
5
Q
B cell receptor endocytosis
A
- When the BCR binds antigen, it is internalized into endosomes
- Proteins bound by the BCR are degraded to peptides and expressed on MHC class II.
6
Q
Potential vaccine design for haptens
A
7
Q
Antibody structure
A
- •Heavy chain
- •Mu (IgM), delta (IgD), gamma (IgG), alpha (IgA), or epsilon (IgE) constant region that determines the isotype
- •Isotype subsets
- •IgG1, IgG2, IgG3, IgG4
- •IgA1, IgA2
- •Isotype subsets
- • Light chain
- •Either a kappa or lambda constant region
8
Q
Fc portion of antibody
A
- •Fc is fragment, crystallizable
- •Mediates many of the effector functions
- •Contains the constant region
- •Many phagocytes have receptors that bind the Fc portion of antibodies
- •Greatly enhances phagocytosis (opsonization)
- •The complement binding region (IgM and IgG) is on the Fc portion of the antibody
- This region only becomes accessible when antigen is bound
9
Q
Fab portion of antibody
A
- •Fab is fragment, antigen-binding
- •Contains the variable regions and the complementarity-determining regions (CDRs)
- •Each B cell makes an antibody with a unique variable region that binds to one antigen (or closely related antigens)
10
Q
Isotypes
Allotypes
Idiotypes
A
-
•Isotypes (classes) are defined by differences in amino acid sequences in the constant regions
- •IgM and IgE are different isotypes
-
•Allotypes are defined by differences between individuals due to genetic polymorphisms
- •Emilio’s IgM and Jane’s IgM are allotypes (same isotype with very minor variations)
- •Idiotypes are defined by the specific amino acids in the hypervariable region
11
Q
IgM
A
- •Mu heavy chain
- •Effectively fixes complement
- •Expressed on the surface as the B cell receptor
- •First antibody produces in an antibody response (primary response)
- •Found as a pentamer to increase avidity (connected by J chains)
- •Does NOT cross the placenta
12
Q
IgD
A
- •Delta heavy chain
- •Expressed on naïve B cell surface
- •There is only trace amounts of IgD in the serum
- •Function is not well understood
13
Q
IgG
A
- •Gamma heavy chain
-
•Most effective antibody class in many infections
- •Opsonizes bacteria
- •Many phagocytes express Fc receptors for IgG
- •Fixes complement
- •Neutralizes bacterial toxins and viruses
- •Most abundant in secondary response
- •Crosses the placenta
14
Q
IgE
A
- •Epsilon heavy chain
- •Antibody dependent cellular cytotoxicity (ADCC)
- •Binds to extracellular parasites
- •Mediates killing by eosinophils (which have receptors for the IgE Fc)
- •Crosslinks IgE Fc receptors on mast cells
- •Release of histamine (allergy and anaphylaxis)
15
Q
IgA
A
- •Alpha heavy chain
-
•Mucosal immunity
- •Prevents attachment of bacteria and virus to mucosal membranes
- •Does NOT fix complement
- •Passively transferred in breast milk to infants
- •Monomeric in serum or dimeric at mucosa (connected/stabilized by J chains)
16
Q
Affinity & Avidity
A
- •Affinity refers to the strength of an individual antibody binding to antigen
- •If the antibodies are multivalent (i.e. the pentameric form of IgM) then the overall strength of the multiple antibodies binding to multiple antigenic sites is the avidity of the interaction
- •Multimeric forms of antibodies serve to increase the avidity of the antibody-antigen interaction
17
Q
Opsonization
A
- •IgG enhances opsonization of encapsulated bacteria through
- •Complement activation (formation of C3b)
- •Direct binding by IgG Fc receptors on phagocytes
- •IgM enhances opsonization through
- •Complement activation
18
Q
Antibody isotype (class) switching
A
- •In the T cell dependent immune response IgM, IgG, IgA, and IgE can be produced.
- •In response to cytokines produced by the T cells and binding of CD40 to CD40L
- •The B cell undergoes gene rearrangement that gives rise to a different isotype of antibody
- •Activation-induced cytidine deaminase (AID) is induced and mediates isotype switchin
- •The class of antibody produced is dependent upon the cytokine produced by the CD4+ T helper cells
- •Interleukin-4 – IgG and IgE
- •Interleukin-5 – IgA
19
Q
Hyper IgM syndrome
A
- •Hyper IgM syndrome occurs when there is a mutation in the gene encoding CD40L on CD4+ helper T cells
- •The B cells cannot effectively class switch and the patients have very high levels of IgM with little IgG, IgA, and IgE
- •The B cell and T cell numbers are normal
- •Decreased/absent germinal centers
- •Patients have severe, recurrent pyogenic bacterial infections
20
Q
T cell dependent (TD) immune response
A
- •Surface IgM BCR recognizes a protein antigen
- •B cells express peptides on MHC class II
- •The T cell-B cell interaction of CD40/CD40L leads to germinal center formation, class switching, and somatic hypermutation
- •Antibodies produced are of high affinity
21
Q
T cell independent (TI) immune response
A
- •B cells recognize a non-protein antigen (e.g. polysaccharide cell wall) which can crosslink surface IgM and activate the B cell
- •TI antigens often have repeated identical antigenic epitopes that causes cross-linking of the BCR complex
- •This can lead to production of secreted IgM (sometimes IgG and IgA) which is specific for the antigen
TI antigen response:
- •Complement (through CD21) and TLR are involved in B cell activation
- •Affinity is generally lower in antibodies derived from a TI immune response
- •Splenic B cells (marginal zone B cells) and mucosal B cells (B1 B cells) are involved in the TI antigen response
22
Q
T cell dependent vs. independent chart with antigens
A
23
Q
Natural Antibodies
A
- •Some antibodies (predominantly IgM) are present prior to exposure
- •Referred to as “natural antibodies”
- •T cell-independent B cell response to environmental antigens
- •Some degree of cross-reactivity between similar antigens
- The most clinically significant natural antibodies arise against the ABO glycoproteins on patient’s with red blood cells lacking the A or B antigen.
- •Antibodies are present without prior exposure to foreign (non-self) red blood cells
24
Q
Humoral Immunity
A
- •Antibodies produced by plasma cells circulate as soluble proteins in the blood to provide protection
- •Some of the protection is mediated by the antibody alone and other mechanisms of protection require involvement by other cell types
- •Exotoxin-mediated diseases
- •Tetanus and diphtheria
- •Infections with polysaccharide capsules
- •Pneumococci, meningococci, Haemophilus influenza
- •Some viral infections
25
Q
Effector functions of antibodies
A
- •Neutralizing toxins
- •Block entry of pathogens into cells and across mucosa
- •Activating the complement cascade (IgG and IgM) through the classical pathway
- •Opsonizing a pathogen or antigen and enhance phagocytosis by other cells (IgG)
-
•Antibody-dependent cytotoxicity (ADCC)
- •Fc receptors expressed on the phagocytic and cytotoxic cells recognize the Fc fragments of the different isotypes
26
Q
IgE-mediated immunity against helminths
A
- •IgE binds to helminths
- •Eosinophils bind to the IgE Fc via FcεRI
- •Binding IgE leads to release of eosinophil mediators to destroy the helminth
- •TH2 CD4+ T cells release IL-5 that enhances eosinophil activity
27
Q
Antibody response to T-cell Independent antigen
A
- •Naïve B cells (Marginal zone B cells or mucosal B cells) recognize antigen through the IgM BCR
- •Co-stimulation occurs through complement receptors (e.g. CD21) and/or TLRs
- •Antigen-specific B cells differentiate to short-lived plasma cells and produce predominantly IgM
- •Limited isotype switch can occur (IgG, IgA)
- •No effective affinity maturation
- •Limited memory
28
Q
Early B cell activation
A
29
Q
Antibody response to T-cell dependent antigen
A
Naïve B cells (outside of the germinal centers)
- •Recognize antigen through the IgM BCR
- •Internalize the antigen on the IgM
- •Degrade antigen to peptides to present on MHC class II
- •Express CD40 and B7 (CD80/86)
- •Can receive additional signals from complement, TLR, CD4+ T cells, and/or cytokines
- •After binding antigen and activation, B cells migrate towards B cell-T cell zone border (secondary lymphoid tissue)
Antigen-activated B cells (B cell-T cell zone border outside germinal center)
- •Interact with antigen-activated CD4+ T helper cells
- •Differentiate to short-lived plasma cells (plasmablasts)
- •Produce and secrete IgM antibody
- •Antibody is relatively low affinity for antigen
Antigen-activated B cells (inside the germinal centers)
- •Further interact with antigen-specific activated CD4+ T helper cells (particularly through CD40:CD40L)
- •Rapidly proliferate
- •Undergo isotype switching and somatic hypermutation
- •Supported by IL-4 and IL-5 (TH2 CD4+ T helper cells)
- •Interact with follicular dendritic cells and antigen-presenting cells to select for high affinity antibody
- •Late germinal center:
- •B cells with high affinity antibodies differentiate into memory B cells or plasma cells
30
Q
Primary antibody response
A
5-10 days
- •The primary antibody response takes about 5-10 days
- •First antibody produced is IgM
- •The earliest IgM produced is specific for antigen, but relatively low affinity
- •After a few days, germinal centers form
- •B cells undergo isotype switching and somatic hypermutation
In the late primary antibody response
- •The high affinity B cells in the germinal center differentiate to plasma cells and memory B cells
- •Antibodies of other isotypes are produced (e.g. IgG)
- •Affinity maturation has occurred
31
Q
Genetic mechanism of isotype switch
A
32
Q
Secondary antibody response
A
1-3 days
- •The secondary antibody response arises from memory B cells and T cells.
- •It occurs much more rapidly (develops in 1-3 days)
- •Leads to a more robust class-switched (IgG) antibody response
33
Q
Increased affinity maturation on repeated exposure
A
- •Successive exposure to a T cell dependent antigen leads to increased affinity of the B cell receptor/antibody
- •After repeat antigen exposure
- •Antigen-specific memory B cells interact with the antigen-specific T cells in the germinal center
- •Somatic mutations and selection lead to increasingly more specific antibodies
34
Q
Feedback inhibition of humoral immunity
A
- •Antigen-antibody complexes can have harmful effects
- •Activate complement through classical pathway
- •IgG production leads to feedback inhibition
- •FcγRIIB on the surface of B cells
- •Binds the Fc portion of IgG
- •Signals through an immunomodulatory tyrosine-based inhibition motif (ITIM)
- •Terminates the B cell response to antigen
35
Q
Peripheral blood antibodies
A
- •IgG >> IgA > IgM > IgD, IgE
- •Evaluation of altered serum antibody levels can help identify immunodeficiency
- •IgD not typically measured
- •IgE requires different techniques
36
Q
X-linked agammaglobulinemia
A
- •Deficiency in Bruton’s tyrosine kinase (required for B cell development)
- •No circulating antibodies, absence of secondary lymphoid tissues
- •Life-threatening infections
- •Encapsulated bacteria
- •Enterovirus
- •Vaccine associated poliomyelitis
37
Q
IgA deficiency
A
- •Most common immunodeficiency
- •Frequently asymptomatic
- •Increased risk for mucosal infections
- •Particularly viral infections
- •Autoimmune association
- •Blood transfusion risk (antibodies against IgA)
38
Q
Activation-induced cytidine deaminase (AID)
A
mediates recombination
39
Q
Common variable immunodeficiency (CVID
A
- •Multiple etiologies and numerous underlying mutations
- •Underlying defect in B cells or helper T cells
- •Overall low immunoglobulins
- •Low IgG, low IgA, and low or normal IgM
- •Decreased memory B cells
- •Increased risk for bacterial, enteroviral and Giardia lamblia infections in late childhood and adulthood
- •Autoimmune association and increased risk for lymphoma
40
Q
Humoral immunity to virus:
A
viral peptides presented on MHC class II
41
Q
Severe Combined Immunodeficiency
A
- •Impaired or absent adaptive immune response
- -No or very limited B cells and T cells +/- NK cells
- -Intact innate immunity
- •Severe, life-threatening infections
- •Different mutations with different disease phenotypes
- -Adenosine deaminase deficiency, RAG gene mutation, common gamma chain (X-linked)
- •Stem cell transplant is the current therapy
42
Q
B cells
A
- CD19+ CD20+
- -Major component of adaptive immunity (humoral immunity)
- -~20% of circulating lymphocytes
- -Express antibody (immunoglobulin) on the cell surface
- -Differentiate into plasma cells and memory cells
- -Antigen-presenting cells
- Originate and mature in BM (and fetal liver)
- Antigen NOT required for early B cell development
- Million produced daily
43
Q
Plasma cells
A
- •Plasma cells (CD38+, CD138+) are responsible for producing antibodies
- •Antibodies are critical for immunity
44
Q
Steps in B cell development
A
- •B cells originate and mature in the bone marrow
- •Antigen is not required for B cell maturation
- •The maturation steps are from lymphoid progenitor to pro-B cell to pre-B cell (μ heavy chains) to immature B cell (IgM BCR) to naïve B cell (IgM and IgD).
45
Q
B cell receptor / Diversity
A
is surface IgM or IgD
Diversity:
- •Each B cell has a BCR specific for one antigen
- •~10 million specificities of BCRs
-
•VDJ recombinase (RAG1 and RAG2 genes)
- -V, D, and J segments for heavy chain
- -V and J segments for light chain
- •RAG1/2 also involved in TCR gene rearrangement
- •RAG1/2 gene mutations can give rise to SCID
- •The B cell receptor (BCR) is an antibody (IgM and IgD in naïve B cells) that has a transmembrane domain and is associated with Igα (CD79a) and Igβ (CD79b)
- •BCR diversity occurs through combinatorial and junctional diversity
- •The variable regions of the heavy chains are formed from VDJ genes and the variable regions of the light chains are formed from VJ genes
- •Successful gene rearrangement and production of IgM is essential for B cell development
46
Q
Junctional diversity of Antibodies
A
- •Nucleotides are added and removed during recombination
- •Occurs at the joining ends of the gene segments
- •Significantly increases diversity of the VDJ and VJ regions
- •These regions are known as “hypervariable regions”
47
Q
Isotype of the antibody
A
- •The isotype of the antibody is determined by the constant region of the heavy chain
- •The constant region genes join to the variable region genes
- •IgM is produced first
- •Successful gene rearrangement and protein production leads to B cell development
48
Q
Clonal deletion
Receptor Editing
A
B cells/ Central tolerance
- -Removal of immature B cells with expression of IgM that is reactive to self
- If the IgM binds to self antigen the cell can die by apoptosis or undergo receptor editing
Receptor Editing: occurs if the BCR binds to self antigen
- -RAG genes are re-expressed
- -the V-J recombination is repeated to express the second type of light chain
- -the new light chain and original heavy chain can generate a specificity that does not recognize self
49
Q
A
50
Q
B cell anergy
A
•B cell anergy (peripheral tolerance)
- -Some self-reactive B cell escape deletion in the bone marrow
- -When it encounters self-antigen in the absence of co-stimulation, the cells becomes anergic (do not respond)
51
Q
Allelic exclusion
A
- •A single B cell expresses protein from only one light chain gene and one heavy chain gene at a time
- •Although alleles from both parents are present, one set of genes is silenced
- •This silencing is known as allelic exclusion
•Each mature B cell/plasma cell only expresses kappa or lambda light chains
- heavy chain variable region is identical in naive B ells with both IgM and IgD
52
Q
Antigen recognition and B cell activation
A
- •The antibody variable region of the BCR recognizes and binds a specific antigen
- •Binding leads to receptor cross-linking in association with Igα/Igβ (CD79a/CD79b) and phosphorylation of ITAMs (Immunoreceptor tyrosine-based activation motifs)
- •ITAM phosphorylation triggers downstream signaling pathways
53
Q
B cell second signal (CD21) or (CD40)
A
—————– CD21————-
- •CD21 (CR2) is a complement receptor expressed with CD19 on the B cell surface
- •CD21 interacts with the C3d complement component bound to antigen (alternative complement pathway)
- •Enhances B cell activation ~1000 fold
- •This can serve as a second signal
—————– CD40————-
- •After binding of antigen, the B cell upregulates co-stimulatory molecules (B7 and CD40)
- •The BCR then takes up the antigen and expresses protein antigens on the MHC class II protein
54
Q
B cells and lymph nodes
A
- •In the germinal center of the lymphoid tissues, antigen activated B cells:
- -Rapidly divide
- -Interact with antigen-specific T cells, APCs, and follicular dendritic cells
- -Undergo isotype switching, somatic hypermutation, and affinity maturation
- •The B cells are antigen-selected in the germinal center
- •Antigen-specific B cells interact with antigen-specific CD4+T cells, antigen-presenting cells, and follicular dendritic cells
- •The B cells mutate the antibody genes to improve binding to antigen
58
Q
•In the germinal center, B cells that are highly specific for antigen differentiate into…
A
•In the germinal center, B cells that are highly specific for antigen differentiate into
- antibody-producing plasma cells
- long-lived memory B cells
68
Q
Mast cells in Hypersensitivity
A
- •Express receptors for Fc portion of IgE (important in anaphylaxis)
- •Release histamine and other cytokines
Histamine is preformed in granules and has immediate effects
- •Vasodilation
- •Increased vascular permeability
- •Smooth muscle contraction
- •Itching
- •Kinins and kininogenase
Additional preformed mediatiors:
- Serotonin
- TNF
- Proteases
- Numerous other molecules
Some that must be produced and have delayed effects:
-
•Arachidonic acid metabolites
- -Leukotrienes: delayed but similar to histamines
- -Prostaglandins
- •Cytokines
- •Chemokines
69
Q
Type I hypersensitivity (Immediate/anaphylactic)
A
Antibody mediated: Very fast, develops in minutes
-
•Cells and antibodies involved
- -Mast cells and basophils
- -Preformed IgE (Prior B cell response driven by TH2 helper T cells)
- •Mechanism
- -First exposure sensitization to form IgE antibodies
- -Subsequent exposure: IgE binds antigen and crosslinks mast cell Fc receptors
- -Mast cells release preformed mediators and produce additional mediators
- Examples: Anaphylaxis, allergic rhinitis, hives
70
Q
Type II hypersensitivity (cytotoxic/antibody-mediated)
A
Minutes to hours, Antibody mediated
-
•Cells and antibodies involved
- -CD8 + cytotoxic T cells, NK cells, and/or neutrophils
- -Preformed IgG/IgM (produced by B cells, driven by TH2 CD4+ helper T cells or naturally-occurring)
-
•Mechanism
- -Preformed IgG or IgM antibody binds to fixed cell surface or extracellular matrix antigens.
- -Binding leads to complement activation and opsonization/phagocytosis and/or antibody-dependent cell-mediated cytotoxicity (ADCC) by NK or CD8+ cytotoxic T cells.
- Examples: Some drug allergies, incompatible blood transfusions, Goodpasture’s syndrome (antibody against basement membrane)
FIgure: ADCC, Complement
71
Q
Type III hypersensitivity (Immune complex-mediated)
A
Hours to days, antibody mediated
-
•Cells and antibodies involved
- -Antigen and antibody complex (typically IgG)
- -Neutrophils
-
•Mechanism
- -When antigen is abundant, soluble immune complexes (antigen bound to antibody) form and deposit in tissues (particularly in vessels)
- -Immune complex deposition can activate complement and lead to inflammation (chemotaxis of neutrophils, vessel leakage, and vessel damage)
- Examples
- •Serum sickness (e.g. drugs)
- •Systemic lupus erythematosus
- •Arthus reaction: -Local injection of antigen that reacts with preformed IgG
72
Q
Type IV hypersensitivity (Delayed-type hypersensitivity)
A
Days to weeks to months
-
•Cells involved
- -Antigen-presenting cells, TH1 CD4+ helper T cells, and sometimes CD8+ cytotoxic T cells
- •Mechanism
- -Antigen-presenting cells prime T cells to respond to antigen and drive a TH1 CD4+ helper T cell response
- -On subsequent response to the antigen, the previously primed T cells (memory cells) proliferate rapidly and activate a macrophage response and cytokine release
- Examples: granuloma formation in TB chronic infection, contact dermatitis (posions ivy), GVHD,
- •In M. tuberculosis and PPD (purified protein derivative) testing, the T cells recognize the microbial peptides.
- •In contact dermatitis (e.g. poison ivy), the T cells recognize chemically modified self proteins.
74
Q
Cytotoxic T cells
A
-
•CD8+ T cells (cytotoxic) mediate direct cellular killing
-
•Perforins and granzymes are present in the granules and released
- •Perforins are inserted into the cell membrane and form a channel
- •Granzymes are proteases that degrade proteins in the cell membrane
-
•Perforins and granzymes are present in the granules and released
- •Activate caspases (leading to apoptosis)
- •FasL is expressed on the cytotoxic T cells that binds to Fas
- •Fas and FasL interact and the target cells dies by apoptosis
76
Q
Activation of effector T cells
A
-
Naïve T cells encounter antigen in the secondary lymphoid organs
- •Antigen receptor engagement as well as co-stimulatory signals are required for activation
- •Typically dendritic cells are the antigen-presenting cells
-
•Effector T cells can encounter antigen in other tissues
- •Antigen receptor engagement but not co-stimulatory signals are required for activation
77
Q
Immune response to intracellular bacteria
A
- •Antigen-presenting cells ingest organisms
- •Recognition of PAMPs by the pattern recognition receptors (e.g. TLRs) stimulates cytokine production (IL-12) and expression of co-stimulatory molecules
- •Pathogen peptides are expressed on MHC class II to CD4+ T helper cells which differentiate to TH1 cells
78
Q
IFNgamma
A
Activates CD8+ and APCs
- •The TH1 CD4+ T cells secrete IFNγ which
- •Activates the APCs to kill the phagocytosed pathogens
- •Activates the CD8+ cytotoxic T cells to become effector cells
- •The CD8+ T cells recognize peptides presented by any nucleated cell and can kill the cells
81
Q
Antigen transmit to secondary lymphoid organs
A
84
Q
NK cells in viral immunity
A
- •NK cells (innate immunity) and interferons are also involved early in the anti-viral immune response
- •NK cells identify infected cells through lack of MHC class I or via ADCC (IgG)
- •NK cells produce cytotoxic proteins (granzyme and perforin) that release and kill the target cell
- NK cells express inhibitory receptors
86
Q
Peptide presentation in MHC class I
A
- •Endogenously synthesized proteins (intracellular proteins) are cleaved by a proteasome to peptide fragments that associate with a TAP (transporter associated with antigen processing) transporter
- •The TAP transporter transports the fragment to the endoplasmic reticulum (ER)
- •Peptide fragments in the ER associate with the MHC class I molecules
87
Q
Peptide presentation in MHC class II
A
- •Extracellular proteins are engulfed by phagocytosis or endocytosis into phagosomes or endosomes respectively
- •The phagosome or endosome will fuse with lysosomes which contain proteases that can degrade the polypeptides into short peptide fragments
- •The peptide fragments are able to associate with the MHC class II molecules in specialized endosomal intracellular vesicles
- MHC class II proteins are prevented from binding to endogenous peptides by binding of a protein called the invariant chain (Ii) in the ER
- •The placement of an extracellularly derived peptide in the MHC class II molecule requires protease removal in specialized endosomal intracellular vesicles
88
Q
Invariant chain
A
89
Q
The role of MHC-associated antigen presentation in the recognition of microbes by CD4+ and CD8+ T cells
A
91
Q
Mycobacterium tuberculosis and granuloma formation
A
- •A pathologic immune response can occur to intracellular pathogens that persist
- •The classic example of cell-mediated immunity that can lead to persistent inflammation is the granulomatous response to M. tuberculosis
- •The chronic antigenic stimulation of the organism drives CD4+ TH1 T cell responses (production of IL-2 and IFNγ)
- •IFNγ drives macrophages to secrete IL-12 and the cycle of activation continues
- •The macrophages secrete hydrolytic enzymes and form granulomas which often have central necrosis
- • These pathways lead to tissue damage, but can keep the organism dormant
delayed type hypersnseitiy and granuloma formation
103
Q
MHC
A
- Proteins responsible for presenting peptides of proteins on the cell surface to T cells
- Antigen presentation occurs when peptide fragments associate with MHC molecules expressed on antigen-presenting cells
- CD4 and CD8 are co-receptors necessary for the TCR to recognize and bind the peptides bound to the MHC molecules
104
Q
CD4 and CD8 with MHC
A
106
Q
cortex medulla of thymus and t cell maturation scheme
A
Cortex: double negative thymocyte selection
- •Early T cell precursors are called thymocytes
- •When the T cell precursor transits from the bone marrow to the thymus it is negative for surface CD3, CD4, and CD8 surface molecules
- -Surface CD3 expression is increased as the thymocytes develop
- •The first stage is in the thymic cortex
- •The first stage is the CD4-CD8- (double negative) stage which does not express a TCR
Double positive thymocyte in the cortex
- •RAG genes are expressed, and produces a TCR with unique antigen specificity
- •The next stage is the double positive (CD4+CD8+) stage
- -Surface CD3 is expressed with the TCR.
- •Cortical epithelial cells express MHC class I and II molecules
- •When the TCR with CD4 or CD8 binds weakly to self-MHC molecules, that cell will survive
Single positive thymocyte in the medulla: negative selection
- •Cortical epithelial cells express MHC class I and II molecules
- •The autoimmune regulator (AIRE) transcription factor synthesizes self proteins to be expressed in the MHC molecules
- •Strong binding of the TCR to self-antigen/MHC molecules: Cell death or becomes regulatory T cell
- •Weak/no binding of the TCR to self-antigen/MHC molecule: Survive and go to periphery
115
Q
3 CD4+ T cell subtypes summary
A
119
Q
2 signal t cell activation (general)
A
FIRST SIGNAL
- •Antigen recognition in the context of the MHC by the TCR
- •After binding of the antigen by the TCR, ITAMs are phosphorylated
- •ITAM phosphorylation recruits and activates ZAP70 tyrosine kinase which triggers a cascade of signaling
- -increased expression of cytokines, cytokine receptors, and cell proliferation genes.
- •The longer the antigen is bound, the more the ITAMs are phosphorylated.
SECOND SIGNAL
- •Binding of activating co-stimulatory molecules or cytokines
- -CD28 is the usual co-stimulatory receptor
- -Cytokines binding to cytokine receptors on the T cells can also provide the second signal
