Immunology Exam 2 Flashcards
Antigenicity
The property of a substance (antigen) that allows it to react with the products of a specific immune response (antibodies)
Immunogenticity
The property of a substance (immunogen) that allows it to provoke an immune response
Immunogens
All immunogens are antigens, but all antigens are not immunogens
Epitope
The region where antigen and antibody, of antigen and TCR bind
Linear epitope
continuous stretch of amino acids
can shapeshift
Conformational epitope
regions of folded protein which cannot shapeshift
hapten
Very small antigen which is able to bind TCR or antibody, but not large enough to provoke a n immune response on its own
Characteristics of immunogens
foreignness- proteins, lipids, etc on the outside of the microbe are not seen as native to the body
molecular size- less than or = to 100,000 causes an immune response; greater than 100,000 causes little to no immune response
Complexity: proteins with basic or aromatic a.a.’s induce stronger immune responses. Polysaccharides tend to be naturally-occuring antigen. nucleic acids are not immunogenic on their own, need to be complexed. Polypeptides- mw~1500 (small asf molecule) molecules also need to be complexed
stability- (flexibility) substance with high flexibility, or low stability are not strong antigens
degradability- best immunogens can be partially degraded for T cell presentation; inert material does not provoke an immune response (hence plastic and metal being used in orthopedic surgeries)
Categories of antigens
Exogenous (“non-human”), exogenous (human), endogenous (“self antigens”), super antigens
exogenous “not human” antigens
microbial; found on surfaces of bacteria, viruses, fungi, parasites, pollutatnt, allergens
exogenous human
alloantigens
alloantigens
antigens from members of same species that distinguish individuals from each other
endogenous “self-antigens”
Immune response should not normally be provoked by self antigens
Super antigens
Toxins that bind nonpolymorphic regions of MHC and invariant portions of TCR
Results in massive T cell activation
Differences between membrane bound antibody (B cell) + TCR
Antibody recognize many types of antigen shapes/conformations/macromolecules. TCRs recognize peptides via MHC. Only recognize infected cells and tumor cells.
Antigen receptor molecules consist of regions/domains
-v=variable=antigen recognition
-c=constant=provide structural stability and bind signal molecules
B lymphocytes can recognize shapes of macromolecules, like proteins, nucleic acids, lipids and carbohydrates
T cells can only recognize peptides bound to MHC
Antigen receptors of Lymphocytes
Antibodies and T cell receptors
What does beta-mecaptiethanol do?
Breaks disulfide bonds in antibodies
What does an antibody contain?
Four polypeptide chains: two identical heavy chains and two identical light chains with each containing a variable and constant region
Structure of an antibody
Each light chain (are 2) is attached to a heavy chain (are 2)
Two heavy chains attached to each other via a disulfide bond
Light chains made up of V and one C domain
Heavy chain has one V and 3 or 4 C domains
Antigen binding site of antibody has V regions of both the heavy and light chains
antibody contains two identical binding sites
CDR
Complementary determining region
Is hypervariable
CDR3 located at the junction of V and C region. Portion of Ig molecule which contributes to binding
Classes of antibodies
Mu IgM, delta IgD, epsilon IgE, gamma IgG, alpha IgA
Differ in C region and have physical, biological and effector properties
What happens when B cells are activated?
Antibodies are secreted, antibodies recognize different types of molecules and enable the humoral immune system to bind and eliminate the microbes and toxins.
What happens when B cells are activated?
Antibodies are secreted, antibodies recognize different types of molecules and enable the humoral immune system to bind and eliminate the microbes and toxins.
Antigen recognizing domains
Variable regions and the conserved portions are constant regions
C and V regions
Within V region sequence variation is short sequences called hyper variable regions or complementarity determining domains (CDRs)
complementarity determining domains (CDRs)
Vary from one receptor to the next and are complementary to the shapes of antigens
By concentrating sequence variation in small regions of the receptor, it is possible to maximize the variability of the antigen binding part while retaining the basic structure of the receptors
Invariant membrane proteins
Associated with antigen receptor polypeptides
Deliver intercellular signals following antigen recognition
Cause a lymphocyte to divide, differentiate, perform effector functions or die
Therefore lymphocytes use different proteins to recognize antigens and to transducer signals in response to antigens which allows variability to be segregated in one set of molecules while leaving the conserved function of signal transduction to other invariant proteins
BCR complex
Set of plasma membrane antigen receptor and associated signaling molecules in B lymphocytes
TCR complex
The analogous set of proteins in T lymphocytes
Binds to MHC
What happens when antigens bind to antigen receptors?
Signaling proteins are P’ed on conserved tyrosine residues by enzymes called protein tyrosine kinases
P causes signaling cascades which results in transcription activation of genes, production of numerous proteins which mediate responses of the lymphocytes
Two forms of antigens
Membrane bound antigen receptors on B cells, secreted proteins
Secreted antibodies
Present in blood and mucus to defend body from microbes
effector molecules of humoral immunity
Are immunoglobulins
Recognize microbial antigens and toxins by their variable domains
Constant regions of secreted antibodies have the ability to bind to other molecules that participate in the elimination of antigens such as proteins of complement system and receptors of other cells (phagocytes, mast cells, NK cells)
Neutralize and eliminate microbes and their toxins in the effector phase of humoral immunity
Immunoglobulins (Igs)
Antibodies
Immunity conferring proteins with the physical characteristics of globulins
Membrane bound antibodies role
Recognize antigens to initiate B cell activation
Cell mediated immunity
Effector function of microbe elimination is performed by T lymphocytes and by other leukocytes responding to T cells
Antigen receptors of T cells are only involved in antigen recognition and T cell activation
Their proteins are NOT secreted and do NOT mediate effector functions
Antibody strucutre
Composed of four polypeptide chains, two identical heavy chains, two identical light chains
Each chain has a variable region and a constant region
Forms a Y shape
Each light chain is attached to a heavy chain
Two heavy chains are fitted together with a double disulfide bond
What does light chain consist of?
Made up of one V chain and one C domain
Are kappa or lambda but not both which differ in C regions
No difference in antigen-binding functions
Contribute to binding and neutralizing of toxins/microbes
What does heavy chain consist of?
Made up of one V and three or four C domains
Immunoglobulin domain (Ig)
When the domains of an antibody fold into a characteristic three dimensional shape
Ig domain consists of two layers of a beta-pleated sheet held together by a disulfide bridge.
Adjacent strands of each beta-sheet are connected by short, protruding loops.
V region of Ig molecules, three of these loops make up three CDRs responsible for antigen recognition
Ig domains without hypervariable regions
In many proteins of the immune system and outside the system
Proteins are involved in responding to stimuli from the environment and from other cells or in adhesive interactions between cells
Proteins are part of the immunoglobulin family
Antigen-binding site of an antibody
Composed of V regions of both the heavy chain and light chain
Core antibody structure contains two identical antigen binding sites
Fab
Whole light chain attached to the V and first C domains of heavy chain
Capable of recognition
Two Fab which attach to one Fc
Binding of Fab neutralizes toxins
Fc
Fragment containing the remaining heavy-chain C domains
Identical in all antibodies
Crystalizes in solution
Binding of Fc region activates other effector functions
Five types of heavy chain proteins
α, δ, ε, γ and μ
IgA, IgD, IgE, IgG, and IgM
Differ in C regions
Gamma chain
1,2,3,4
alpha chains
1,2
IgA
C region is alpha 1,2
Does not activate complement not an opsonin
Mainly a dimer, or monomer, trimer
Mucosal immunity because it is secreted
Secreted in breastmilk
Effector function is bacteria and viruses and prevents them from entering the tissue
IgD
No effector function on its own but it is necessary for B cell activation
Monomer
Naive B cell antigen receptor with IgM
Delta heavy chain
When IgM+IgD bind to antigen and are stimulated by T helper cells
Antigen specific B cell clone expands and differentiates which makes more IgM
IgM+IgD+ helper T cells causes B cell expansion and differentiation
Plasma cells secrete IgM and also produce antibodies of other heavy chain classes (heavy chain class or isotope switiching)
IgE
Effector-binds to antigen to induce signal transduction in mast cells. Mast cell activation occurs (mucus membranes)
Immediate hypersensitivity
epsilon heavy chain
Increased [ ] in parasitic infections and allergic reactions
Monomer
Binds CH4 region
Mast cell coated with IgE in respiratory tract encounters allergens and binds allergens
Mast cells degranulates releasing histamine which causes allergic rhinitis
IgE binds parasite= mast cell is called in and binds IgE tail, degranulates
IgG
Subtypes are gamma 1,2,3,4 because of slight difference in amino acid structure
1,3,4 cross the placenta
1,3 activate complement, act as opsonins
80% Igs
Found equally in tissue fluid and blood
effector- bind/activates complement, strong opsonin
Resolution of infection
Important in secondary immune response
IgM
Active infection marker
6% of Igs
First antibody produced during development and first one at infection
Mostly found in blood
Can hangout in mucus membranes
Effector cells bind bacteria, viruses
Strong aglutinador
Binds and activates complement
Not an opsonin b/c it is so huge a phagocyte cannot eat it!!
Is a monomer as B cell receptor, becomes pentamer when secreted
Heavy-chain class/isotope class switching
Change in Ig isotope production
Affinity
The strength with which one antigen binding site of an antibody binds to one epitope of an antigen
Increases with repeated stimulation
Affinity maturation
Increase in antigen-binding strength
Avidity
The total strength of binding is much greater than the affinity of a single antigen-antibody bond
Cross-reaction
When antibodies produced against one antigen bind another, structurally similar antigens
Monoclonal antibodies
Obtained from an animal immunized with an antigen
Then you get one specific antibody
Hybridomas
Hybrids of B cells and myeloma cells
Produce antibodies and grow continuously
We replace animal Ig with human Ig to not cause an immune response
Can also replace Ig genes of mice with human antibody genes and immunize mice with antigen to make specific human antibodies
TCR
recognizes antigens and MHC molecule
Consists of a V and C region
Has alpha and beta chain (specific recognition of MHC molecules and bound peptides
three complementary determining regions each corresponding to a loop in the V domain
Incapable of transmitting signal to T cells
CD3 and Zeta (wiggle wiggle) chains
associated with TCR to make TCR complex
Initiates signaling when TCR recognizes antigen
What is needed for T cell activation?
engagement of coreceptor molecules CD4 or CD8 (recognizes nonpolymorphic regions portions of MHC molecules
Difference between antigen recognition between B and T lymphocytes
Antibodies can bind to different chemical structures with high affinity to neutralize toxins present in low concentrations
Heavy chain is membrane-anchored
Are secreted
TCR only recognize peptide-MHC complexes and bind with low affinity
Affinity is strengthened by other cell adhesion molecules
Both TCR chains are anchored to PM
Are not secreted, do not undergo affinity maturation or do not have isotopes to which switching can occur
Gamma delta TCR
5-10% of T cells express this
Recognize variety of protein and non protein antigens that are not displayed by MHC.
Are in epithelia
Natural killer T cells (NK-T cells)
5% of all T cells
Express alpha beta TCRs and surface molecules of NK cells
Express alpha beta TCRs with limited diversity, recognize lipid antigens displayed by nonpolymorphic class I MHC like molecules called CD1
MAIT cells
Subset of T cells
Mucosal associated invariant T cells
alpha beta TCRs with limited diversity
TCRs are specific for bacterially derived vitamin B metabolites bound to an MHC-like protein called MR1
Account for 5% of blood, 20-40% of liver T cells
Types of T cells
gamma delta T cells, NK-T cells, MAIT cells
Lymphocyte devlopment
Commitment in bone marrow of hematopoietic pro-stem cells to B or T cell lineage -> associated with activation of several lineage specific transcription factors and increased accessibility of Ig and TCR genes to the gene recombination machinery
Proliferation and survival of progenitor cells -> Beginning to become pre-T or B-cells. Is stimulated by growth factors produced by stromal cells in the bone marrow and the thymus
IL-7 maintains and expands the number of progenitors before they express their receptors. More proliferation occurs after they complete their first antigen receptor gene rearrangement, assemble a pre-antigen receptor.
Pre-antigen receptor functions as quality control and only functional cells are preserved
Rearrangement (recombination) and expression of antigen receptor genes
Selection events to preserve and expand cells that express potentially useful antigen receptors
Selection of lymphocytes
positive and negative selection
Positive selection of lymphocytes
allows only cells with functional receptors to complete maturation
negative selection of lymphocytes
kills off cells with high affinity for self-antigens
Germline organization of antigen receptor gene loci
Contain coding and non coding segments
Ig heavy chain C regions and TCR C regions consist of multiple exons
Germline Inherited configuration
Lymphoid progenitors contain Ig (Antibodies= Immunoglobulin Ig) and TCR gene segments
V region gene segments (30-40)
C region has one or few genes
What are between V and C regions?
Groups of several short coding sequences
D (diversity) , J (joining) segments
All antigen receptor gene loci in B cells and alpha beta T cells contain V, J, C gene segments
Only Ig heavy chain and T cell receptors beta chain also contain D segment
Kappa and Lambda
What happens following commitment of lymphocyte progenitor to B lymphocyte?
Randomly selected Ig heavy chain D gene segment recombines with J segment to form DJ complex.
V segment is joined and fused to make recombined VDJ exon in heavy-chain locus
Gene is transcribed, in primary RNA transcript, VDJ exon is spliced in C region exons of micro chain, the most 5’ C region in the Ig chain heavy gene locus to form micro mRNA
The m RNA is translated to make micro heavy chain which is the first Ig protein made during B cell maturation
In light chains there is no D segment so the V and J segments recombine
Somatic recombination
VDJ recombination
Lymphoid specific enzyme, VDJ recombinase, composed of recombination activating gene 1 and 2 (RAG-1 and RAG-2)
Recombination takes place within conserved sequences upstream or downstream of gene segments called Recombination Signal Sequences (RSS)
Recombination begins by the binding of RAG-1/RAG-2 to RSS. This cuts one strand of DNA
5’ cut end of the cut strand reacts with the uncut strand to form a double stranded break and a hairpin formation
The heptamer sequences are ligated and an endonuclease (ARTEMIS) cleaves the hairpin at a random site
Once the complementary nucleotides to this strand have been added to form a palindrome sequence
The enzyme TdT fills the gap with N nucleotides added at random
The processed coding ends are ligated together by DNA ligase IV
This process of recombination of different gene segments and addition of P and N nucleotides leads to many different antigen specificities
Combinatorial diversity
Use of different recombination of V, D, and J gene segments in different clones of lymphocytes
Limited by number of available V, D, and J segments
Junctional diversity
Changes in nucleotide sequences introduced at the junctions of the recombining V, D, and J gene segments
Unlimited
Produced by three mechanisms which generate more sequences than are present in the germline genes
VDJ recombinase
Only expressed in immature B and T lymphocytes
Ig light and heavy chains are rearranged in B cells, alpha and beta genes are rearranged in T cells
mediates the somatic recombination of V and J ir of V, D and J gene segments
Double stranded DNA breaks
Brings Ig or TCR gene segments close together and cleaves the DNA at specific sites
Involves the formation of hairpin loops that are opened by an enzyme called ARTEMIS
Genes are then enzymatically ligated
Makes full length VJ or VDJ exon without intervening DNA segments
B lineage specific transcription factors
Make Ig gene loci (kappa or lambda) accessible to the VDJ recombinase but not the TCR loci
Transcriptional regulators in T cells
In developing T cells they help to open the TCR loci but not the Ig loci. The open loci are the one accessible for the recombinase
How do we get diversity of antigen receptors?
Combinatorial and Junctional Diversity
Three mechanisms by which junctional diversity is produced
- Exonucleases remove nucleotides from V, D, and J gene segments at the sites of recombination
- lymphocyte-specific enzyme called terminal deoxyribonucleotidyl transferase (TdT) catalyzes random addition of nucleotides that are not part of germline genes to the junctions between V and D segments and D and J segments making N regions
- During DNA repair ARTEMIS cuts hairpin loops forming overhanging DNA sequences. Overhands are filled in with new nucleotides (P-nucleotides) which make new coding sequences not in the germ line DNA, thereby introducing additional variability at the sites of recombination
Early steps in B cell maturation
Ig heavy chain rearranges first and only cells that make an Ig micro heavy-chain protein are selected to survive and become pre-B cells
Ig recombination occurs after pro-B cells stop dividing making DJ and then VDJ complex
Cells to successfully make functional heavy-chain gene rearrangements and synthesize Ig heavy chain micro protein are pre-B cells
Also have micro protein on cell surface that work with two other invariant light chains called surrogate light chains (resemble light chains)
This complex of micro chain and surrogate light chains associate with Ig alpha and Ig beta signaling molecules to for the pre-BCR
Pro-B cells
Earliest proliferating progenitors committed to the B cell lineage
Pre-B cells
Cells to successfully make functional heavy-chain gene rearrangements and synthesize Ig heavy chain micro protein
Role of pre-BCR complex in B cell maturation
First checkpoint: signals from pre-BCR promote survival and proliferation of B lineage cells that have made the rearrangement of the Ig H chain locus. This checkpoint selects and expands the pre-B cells that express a functional micro heavy chain.
Pre-B cells that fail to make non productive arrangements at the H locus fail to make micro protein and cannot express a BCR or receive pre-BCR signals. Die via apoptosis
The pre-BCR complex signals the shut off of recombination of Ig H chains on the second chromosome so then each B cell can express an Ig heavy chain from one of the two inherited parental alleles (allelic exclusion = ensures that each cell can only express a receptor of a single specificity
Pre-BCR induces V and J rearrangements of the the K light-chain gene, leading to the production of K proteins and assembly of surface IgM
When is lambda light chain produced?
lambda light chain is produced only if both rearranged kappa chain loci fail to express a functional protein or if the k chain generates a self-reactive receptor
Immature B cells
Have second checkpoint: BCR complex delivers signals to ensure survival of cells with antigen receptors
The signal stops recombinase production and further recombination of the light-chain loci.
This results in B cells having either a kappa or lambda light chain from one of the inherited alleles
Late steps of B cell maturation
Immature B cells leave bone marrow and go the the spleen where they need to have both IgM and IgD receptors in order to respond to an antigen
Maturation of B lymphocytes
HSC:
No Ig proteins
Pro-B:
No Ig proteins
D to J rearrangement of the Ig H chain
Large Pre-B:
V to DJ rearrangement of the H chain
Has Pre-BCR Ig proteins
Small Pre-B:
Rearranged VDJ of Ig H chain
V to J rearrangement of the Ig L chain
Intracellular micro Ig protein
Immature B:
Rearranged VDJ of Ig H chain
Rearranged VJ of Ig L chain
IgM
Mature B:
Rearranged VDJ of H chain
Rearranged VJ of light chain
IgM, IgD
Positive selection of mature B cells
Are selected based on the expression of complete antigen receptors
Negative selection of mature B cells
If an immature B cell binds an antigen in the bone marrow with high affinity, it may re-express the VDJ recombinase enzyme, undergo light chain VJ recombination, make a different light chain, chain specificity of the receptor called receptor editing
Immature B cells that attack antigens in the periphery die by apoptosis because self antigens are in the periphery. Negative selection ensures there are no dangerous cells that react to self antigens
Selection of mature B cells
Selected positively for the expression of functional receptors and selected negatively against strong recognition of self antigens
Where does T cell maturation occur?
When the T cell progenitors migrate from the bone marrow to the thymus
T cell maturation
Stem cells:
Pro-T (double negative T cells):
No CD4 or CD8 receptor
TCR beta recombination mediated by VDJ recombinase
Pre-T:
V beta to DJ beta gene arrangements
germline alpha
Pre TCR
No CD4 or CD8 receptor
Double positive:
V alpha to J alpha TCR gene rearrangement
Alpha beta TCR protein gene expression
CD4 and CD8 surface markers
TCR/CD3lo
Single positive:
alpha beta TCR
CD4 with no CD8
or
CD8 with no CD4
TCRs/CD3hi
Maure T cell:
alpha beta TCR
CD4 with no CD8
or
CD8 with no CD4
TCRs/CD3hi
What does IL-7 do to pro-T cells?
The cells will expand in number
IL-7 is made by the thymus
What happens if VDJ recombination is successful in pro-T cells?
Happens in one of the two inherited TCR beta chain loci
If the TCR beta chain protein is synthesized, it is expressed on cell surface associated with an invariant protein pre-T alpha to form the pre-TCR complex of pre-T cells
What happens if VDJ recombination fails in pro-T cells?
Recombination will take place on the other locus and not on one of the two inherited loci
If that fails and a TCR beta chain is not made, then the pro-T cell dies
Pre-TCR complex
Intracellular signals to allow the cells to survive and proliferate like in B cell maturation
Get TCR alpha gene recombination
Get the inhibition of VDJ recombination in the second beta chain locus (allelic exclusion)
What happens when the alpha chain and complete TCR is not expressed in pre-T cells?
Death of cell
What happens when the alpha chain and complete TCR is expressed on pre-T cells?
Surviving cells express complete TCR alpha beta TCR and have both CD4 and CD8 receptors (double positive T-cells)
Purpose of T cell selection
Eliminate cells incapable of recognizing individual MHC molecules
Positive selection of T cells
If the TCR of the T cell recognizes an MHC molecule in the thymus with a moderate to low affinity
Become committed to functional fates: CD8+ cells will differentiate into CDLs upon activation and CD4+ cells will differentiate into cytokine-producing helper T cells
If the T cell self recognizes with low avidity then it is possible for it to recognize a foreign antigen peptide presented by MHC more strongly
What happens to baby T cells that do not recognize MHC molecules?
Die
How do we get single positive T cells from double positive T cells
T cells that recognize class I MHC will keep the expression of CD8 and will lose expression of CD4 which identifies class II MHC
Same thing happens to T cell that identifies class II MHC. Will lose CD8 expression and will keep CD4 expression
Single-positive T cells emerge
What happens to immature double positive T cells that strongly recognize MHC-peptide complexes in thymus cortex?
Apoptosis
Process of negative selection
Role of negative selection in T cell maturation
Serves to eliminate potentially dangerous T cell lymphocytes
What cells become T regulatory cells?
Immature CD4+ cells that recognize self antigens in the thymus with intermediate avidity
Not known why
What happens when microbes are resistant to phagocytosis and can replicate?
CD4+ helper cells enhance the ability of macrophages to kill injected microbes
What destroys parasites
eosinophils and IgE
CD4+ helper cells produce cytokines to recruit and activate leukocytes to destroy the microbes
How do viruses infect?
They infect and replicate in cells
Life cycles of the viruses take place in cytosol and nucleus
CD8+ cells kill these cells
Responses of naive T lymphocytes
- Secretion of cytokines needed for proliferation and differentiation. IL-2 produced by antigen activated T cells stimulated proliferation resulting in clonal expansion (rapid increase of antigen-specific leukocytes)
- Turn from naive to effector cells
- Leave lymphoid organs and enter circulation to go to sites of infection. Some remain in secondary organs where they give signals to B cells to promote antibody response
- Memory cells are made. Circulate in blood or reside in tissues for years
- As effector T cells eliminate pathogen, the stimuli that cause T cell expansion stops. All efector cells die and memory cells remain
Differences between naive and effector T cell migration patterns through tissues
Naive T lymphocytes constantly recirculate through secondary lymphoid organs until a dendritic cell shows T cell an antigen peptide via MHC
Activated T cells leave secondary organ to go to tissue where this is a site of infection
How do T cells recognize antigens?
TCR recognizes antigen peptide
CD4 or CD8 attaches to MHC molecules to help TCR deliver activating signals
Adhesion molecules strengthen binding of T cells to APCs
Costimulators expressed on APCs (dendritic cells) bind to their own receptors on the T cell to promote responses
Cytokines from other cells bind to T cell receptors to amplify T cell response. Then they can differentiate into different cells
What causes the first signal for T cell activation?
When TCR and CD4 or CD8 coreceptors recognize complexes of peptide antigens and MHC molecules
Do gamma and zeta chains on TCR recognize MHC complexes?
Do not recognize MHC complexes
How are gamma and zeta chains activated?
CD4 or CD8 binds MHC complex which brings signaling enzymes closer to the CD3 and zeta chains to initiate signal transduction
How are signals caused to lead to T cell activation?
Signals are triggered by a set of proteins linked to the TCR
TCR alpha beta
recognizes antigens
cannot transmit signals to the interior of the cell
Signaling proteins that are associated with the TCR complex
Three CD3 proteins and zeta chain
Are invariant in all T cell types
What makes up TCR complex?
TCR, CD3 and zeta chains
Super antigens
Bind to MHC molecules and TCRs
Engage more TCRs than normal antigens do
Activate TCRs regardless of peptide-MHC specificity
Cause activation of a large number of T cells with excessive cytokine release and systemic inflammatory disease
TCR
antigen recognition
Binds to peptide MHC
expressed on T cells
CD3
On all T cells
Helps with sending out signals for T cell activation
Zeta chains
Signal transduction by TCR complex
Are on T cels
CD4
Coreceptor: delivers activating signals
Binds to class II MHC which are on APCs
CD8
Coreceptor
Bind to class I MHC on APCs
CTLA-4
Inhibitor: Blocks costimulatory signals
Binds to B7-1/B7-2 on APCs
CD28
Costimulatory receptor: delivers activating signals
Binds to B7-1/B7-2 on APCs
PD-1
Inhibitor: Blocks costimulatory signals and TCR signals
Binds to PD-L1/PD-L2 on tissue and tumor cells
LFA-1
Adhesion molecule that binds to ICAM-1 on APCs and endothelium
Role of adhesion molecules in T cells
Recognize their ligands on APCs and stabilize binding of T cells to the APCs
Since TCR binds antigens with low affinity adhesion molecules make the binding stable just enough to make necessary signaling threshold
Are on T cells that bind ligands on APCs
Integrin
Adhesion molecule on T cells
Leukocyte function-associated antigen 1 (LFA-1) binds to intracellular adhesion molecule 1 (ICAM-1) on APCs
When T cell recognizes peptide there is an increase of LFA-1 affinity which increases the T cell binding to the peptide antigen
Direct migration of effector T cells to go to sites of infection
Costimulators
B7-1 (CD80) and B7-2 (CD86) which is increased when APCs encounter microbes
B7 are recognized by CD28 receptor on T cells
Costimulators like this one inhibit immune responses
CD28
receptor on T cells
essential for responses of naive T cells
What would happen without CD28:B7 reactions?
Antigen recognition by the TCR is not enough for initiating T cell responses
Microbes stimulate the expression of B7 costimulators on APCs
Ensures T cells are only activated by microbes and not harmless foreign substances
Prevents autoimmunity
ICOS
Inducible costimulator
Homologous to CD28 and expressed on T cells
Helps in dev. and function of follicular helper T cells
CD40
Expressed on activated T cells that activates the APCs to express more B7 costimulators and to secrete cytokines like IL-12 which enhance T cell diff.
Adjuvants
Induce expression of costimulators on APCs to secrete cytokines to activate T cells
Are products of microbes or something that mimics microbes
Bind to toll-like receptors and NOD-like receptors
Used in vaccines
Trick immune system to have an immune response
What do agents that block CD28:B7 interactions cause?
Used in treatments of disorders in which T cell activation causes organ dysfunction, autoimmune diseases, graft rejection
What helps activate CD8 cells?
CD4 cells
HIV kills CD4 cells which makes less CD8 cells able to be activated to kill the infection
LCK
Initiates signal cascade after antigen recognition to activate T cells
protein tyrosine kinase
Is brought close to ITAMs by TCR complex to phosporylates them
Immunoreceptor tyrosine-based activation motifs (ITAMs)
Are on CD3 and zeta chains on T cells
LCK is brought close to the TCR complex phosphorylates these residues
Therefore initiates signal transduction of T cells
P’ed ITAMs are a docking site of the Zeta chain for tyrosine kinase ZAP-70
ZAP-70
When P’ed it P’s adaptor proteins and enzymes which assemble at TCR complex to mediate other signaling events
Signaling pathways linked to the TCR complex
Lead to production of functional transcription factors
Nuclear factor of activated T cells (NFAT) and the RAS/RAC-MAP kinase pathways
Nuclear factor of activated T cells (NFAT) pathway
Inactive phosphorylated form in the cytosol of resting T cells
Is calcium dependent
Initiated by the activation of phospholipase C-gamma (PLC-gamma) enzyme by ITK kinase. Attaches itself to one of the adaptor proteins
Activated PLC-gamma catalyzes hydrolysis of plasma membrane phospholipid (PIP2). PIP2 is broken down to IP3 which binds to IP3 receptor on ER
Initiates release of Ca2+ into the cytosol
Plasma channel for Ca2+ is opened from loss of Ca2+ in ER
More Ca2+ in cytosol activates phosphatase cineurin
The enzyme removes P’s from NFAT which allows txn factor to go to the nucleus where it binds to promoters of IL-2 gene and components of IL-2 receptor
RAS/RAC-MAP kinase pathways
GTP binds to RAS, RAC and adaptor proteins and enzymes which eventually activate MAP kinases
Pathways are initiated by ZAP-70 dependent phosphorylation and accumulation of adaptor proteins at PM which recruits RAS or RAC
Activation by GTP of these proteins leads to activation of different MAP kinases
Terminal of kinase is called ERK
Calcineurin inhibitors
drugs that block phosphatase activity of calcineurin to suppress NFAT-dependent production of cytokines by T cells
Used to prevent graft rejection
What enhances the expression of T cell genes?
When ERK and JNK is activated in RAS/RAC pathway they induce cFOS protein which and the P’ion of cJUN protein. The two proteins combine to form transcription activator protein 1 (AP-1) which enhances txn and several T cell genes
What do CD28 signals do?
They increase the production of survival factors, IL-2 and cell cycle inducers, all of which promote survival and proliferation of activated T cells and their differentiation into effector and memory cells
What do CD4+ cells secrete?
IL-2
cytokines are mainly secreted by these cells
Can naive T cells bind to IL-2
No, IL-2 has three chains. Naive T cells only have beta and gamma chain. Active T cells have alpha chain as well which allows them to bind to IL-2 with a high affinity
Activation causes secretion of more IL-2 which is an example of autocrine signaling
IL-2
stimulate and help proliferate T cells
means more antigen specific T cells
High affinity for it on regulatory cells and is important for maintenance of regulatory cells
Binding of IL-2 initiates proliferation
Subsets of T cells
Th1, Th2, Th17
Leave lymphoid organs and go to site of infection
Others stay in lymphoid organs and migrate into lymphoid follicles where they become T follicular helper (Tfh) cells
Memory cells circulate through the blood
How do CD4+ helper cells activate phagocytes and B lymphocytes?
Actions of PM protein CD40L and secreted cytokines
What does IL-7 and IL-15 do for memory cells?
They are made by stromal and myeloid cells in tissues and keep memory cells alive and cycling slowly
Can memory T cells make cytokines?
Yes, they do and can also kill infected cells
No effector function until they encounter an antigen
More rapid response time than naive lymphocytes and make larger secondary responses
Different types of memory cells and their functions
central memory cells: populate lymphoid organs and are responsible for rapid clonal expansion after reexposure to antigen
effector memory cells: are in mucosal and other peripheral tissues and mediate rapid effector functions when they recognize an antigen. Have the ability to exit the tissue and recirculate
tissue-resident memory cells: reside in skin and mucosal tissues and do not readily enter circulation. Mediate rapid secondary responses to antigens in the tissues
All memory cells do not require activation by presentation of a dendritic cell. Do not require high levels of costimulation. B cells and macrophages can activate memory T cells
CTLA-4
In secondary lymphoid organs
B7 binding protein on CD4+ cells and T reg cells which suppresses activation of responding T cells
Blocks and moves B7 molecules from surface of APCs
Reduces costimulation of CD28!
Has better binding affinity to B7 molecules than CD28
Effective when B7 levels are low
Tregulatory mediated suppression of immune response
PD-1
Expressed on CD8+ and CD4+ which inhibit effector phase
It is P’ed when it recognizes PD-L1/PD-L2 which function like B7
After P’ing the tyrosine’s in the PD-1 tail bind a tyrosine phosphatase that inhibits kinase-dependent activation signals from CD28 and the TCR complex
PD-1 is increased by cytokines that are made after prolonged inflammation
