Immunology Exam 2 Flashcards

(160 cards)

1
Q

Antigenicity

A

The property of a substance (antigen) that allows it to react with the products of a specific immune response (antibodies)

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2
Q

Immunogenticity

A

The property of a substance (immunogen) that allows it to provoke an immune response

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3
Q

Immunogens

A

All immunogens are antigens, but all antigens are not immunogens

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4
Q

Epitope

A

The region where antigen and antibody, of antigen and TCR bind

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5
Q

Linear epitope

A

continuous stretch of amino acids
can shapeshift

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6
Q

Conformational epitope

A

regions of folded protein which cannot shapeshift

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7
Q

hapten

A

Very small antigen which is able to bind TCR or antibody, but not large enough to provoke a n immune response on its own

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8
Q

Characteristics of immunogens

A

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)

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9
Q

Categories of antigens

A

Exogenous (“non-human”), exogenous (human), endogenous (“self antigens”), super antigens

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10
Q

exogenous “not human” antigens

A

microbial; found on surfaces of bacteria, viruses, fungi, parasites, pollutatnt, allergens

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11
Q

exogenous human

A

alloantigens

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12
Q

alloantigens

A

antigens from members of same species that distinguish individuals from each other

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13
Q

endogenous “self-antigens”

A

Immune response should not normally be provoked by self antigens

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14
Q

Super antigens

A

Toxins that bind nonpolymorphic regions of MHC and invariant portions of TCR
Results in massive T cell activation

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15
Q

Differences between membrane bound antibody (B cell) + TCR

A

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

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16
Q

Antigen receptors of Lymphocytes

A

Antibodies and T cell receptors

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17
Q

What does beta-mecaptiethanol do?

A

Breaks disulfide bonds in antibodies

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18
Q

What does an antibody contain?

A

Four polypeptide chains: two identical heavy chains and two identical light chains with each containing a variable and constant region

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19
Q

Structure of an antibody

A

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

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20
Q

CDR

A

Complementary determining region
Is hypervariable
CDR3 located at the junction of V and C region. Portion of Ig molecule which contributes to binding

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21
Q

Classes of antibodies

A

Mu IgM, delta IgD, epsilon IgE, gamma IgG, alpha IgA
Differ in C region and have physical, biological and effector properties

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22
Q

What happens when B cells are activated?

A

Antibodies are secreted, antibodies recognize different types of molecules and enable the humoral immune system to bind and eliminate the microbes and toxins.

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23
Q

What happens when B cells are activated?

A

Antibodies are secreted, antibodies recognize different types of molecules and enable the humoral immune system to bind and eliminate the microbes and toxins.

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24
Q

Antigen recognizing domains

A

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)

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25
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
26
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
27
BCR complex
Set of plasma membrane antigen receptor and associated signaling molecules in B lymphocytes
28
TCR complex
The analogous set of proteins in T lymphocytes Binds to MHC
29
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
30
Two forms of antigens
Membrane bound antigen receptors on B cells, secreted proteins
31
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
32
Immunoglobulins (Igs)
Antibodies Immunity conferring proteins with the physical characteristics of globulins
33
Membrane bound antibodies role
Recognize antigens to initiate B cell activation
34
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
35
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
36
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
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What does heavy chain consist of?
Made up of one V and three or four C domains
38
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
39
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
40
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
41
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
42
Fc
Fragment containing the remaining heavy-chain C domains Identical in all antibodies Crystalizes in solution Binding of Fc region activates other effector functions
43
Five types of heavy chain proteins
α, δ, ε, γ and μ IgA, IgD, IgE, IgG, and IgM Differ in C regions
44
Gamma chain
1,2,3,4
45
alpha chains
1,2
46
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
47
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)
48
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
49
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
50
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
51
Heavy-chain class/isotope class switching
Change in Ig isotope production
52
Affinity
The strength with which one antigen binding site of an antibody binds to one epitope of an antigen Increases with repeated stimulation
53
Affinity maturation
Increase in antigen-binding strength
54
Avidity
The total strength of binding is much greater than the affinity of a single antigen-antibody bond
55
Cross-reaction
When antibodies produced against one antigen bind another, structurally similar antigens
56
Monoclonal antibodies
Obtained from an animal immunized with an antigen Then you get one specific antibody
57
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
58
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
59
CD3 and Zeta (wiggle wiggle) chains
associated with TCR to make TCR complex Initiates signaling when TCR recognizes antigen
60
What is needed for T cell activation?
engagement of coreceptor molecules CD4 or CD8 (recognizes nonpolymorphic regions portions of MHC molecules
61
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
62
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
63
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
64
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
65
Types of T cells
gamma delta T cells, NK-T cells, MAIT cells
66
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
67
Selection of lymphocytes
positive and negative selection
68
Positive selection of lymphocytes
allows only cells with functional receptors to complete maturation
69
negative selection of lymphocytes
kills off cells with high affinity for self-antigens
70
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
71
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
72
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
73
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
74
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
75
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
76
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
77
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
78
B lineage specific transcription factors
Make Ig gene loci (kappa or lambda) accessible to the VDJ recombinase but not the TCR loci
79
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
80
How do we get diversity of antigen receptors?
Combinatorial and Junctional Diversity
81
Three mechanisms by which junctional diversity is produced
1. Exonucleases remove nucleotides from V, D, and J gene segments at the sites of recombination 2. 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 3. 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
82
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
83
Pro-B cells
Earliest proliferating progenitors committed to the B cell lineage
84
Pre-B cells
Cells to successfully make functional heavy-chain gene rearrangements and synthesize Ig heavy chain micro protein
85
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
86
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
87
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
88
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
89
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
90
Positive selection of mature B cells
Are selected based on the expression of complete antigen receptors
91
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
92
Selection of mature B cells
Selected positively for the expression of functional receptors and selected negatively against strong recognition of self antigens
93
Where does T cell maturation occur?
When the T cell progenitors migrate from the bone marrow to the thymus
94
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
95
What does IL-7 do to pro-T cells?
The cells will expand in number IL-7 is made by the thymus
96
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
97
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
98
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)
99
What happens when the alpha chain and complete TCR is not expressed in pre-T cells?
Death of cell
100
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)
101
Purpose of T cell selection
Eliminate cells incapable of recognizing individual MHC molecules
102
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
103
What happens to baby T cells that do not recognize MHC molecules?
Die
104
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
105
What happens to immature double positive T cells that strongly recognize MHC-peptide complexes in thymus cortex?
Apoptosis Process of negative selection
106
Role of negative selection in T cell maturation
Serves to eliminate potentially dangerous T cell lymphocytes
107
What cells become T regulatory cells?
Immature CD4+ cells that recognize self antigens in the thymus with intermediate avidity Not known why
108
What happens when microbes are resistant to phagocytosis and can replicate?
CD4+ helper cells enhance the ability of macrophages to kill injected microbes
109
What destroys parasites
eosinophils and IgE CD4+ helper cells produce cytokines to recruit and activate leukocytes to destroy the microbes
110
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
111
Responses of naive T lymphocytes
1. 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) 2. Turn from naive to effector cells 3. 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 4. Memory cells are made. Circulate in blood or reside in tissues for years 5. As effector T cells eliminate pathogen, the stimuli that cause T cell expansion stops. All efector cells die and memory cells remain
112
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
113
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
114
What causes the first signal for T cell activation?
When TCR and CD4 or CD8 coreceptors recognize complexes of peptide antigens and MHC molecules
115
Do gamma and zeta chains on TCR recognize MHC complexes?
Do not recognize MHC complexes
116
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
117
How are signals caused to lead to T cell activation?
Signals are triggered by a set of proteins linked to the TCR
118
TCR alpha beta
recognizes antigens cannot transmit signals to the interior of the cell
119
Signaling proteins that are associated with the TCR complex
Three CD3 proteins and zeta chain Are invariant in all T cell types
120
What makes up TCR complex?
TCR, CD3 and zeta chains
121
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
122
TCR
antigen recognition Binds to peptide MHC expressed on T cells
123
CD3
On all T cells Helps with sending out signals for T cell activation
124
Zeta chains
Signal transduction by TCR complex Are on T cels
125
CD4
Coreceptor: delivers activating signals Binds to class II MHC which are on APCs
126
CD8
Coreceptor Bind to class I MHC on APCs
127
CTLA-4
Inhibitor: Blocks costimulatory signals Binds to B7-1/B7-2 on APCs
128
CD28
Costimulatory receptor: delivers activating signals Binds to B7-1/B7-2 on APCs
129
PD-1
Inhibitor: Blocks costimulatory signals and TCR signals Binds to PD-L1/PD-L2 on tissue and tumor cells
130
LFA-1
Adhesion molecule that binds to ICAM-1 on APCs and endothelium
131
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
132
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
133
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
134
CD28
receptor on T cells essential for responses of naive T cells
135
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
136
ICOS
Inducible costimulator Homologous to CD28 and expressed on T cells Helps in dev. and function of follicular helper T cells
137
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.
138
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
139
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
140
What helps activate CD8 cells?
CD4 cells HIV kills CD4 cells which makes less CD8 cells able to be activated to kill the infection
141
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
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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
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ZAP-70
When P'ed it P's adaptor proteins and enzymes which assemble at TCR complex to mediate other signaling events
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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
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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
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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
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Calcineurin inhibitors
drugs that block phosphatase activity of calcineurin to suppress NFAT-dependent production of cytokines by T cells Used to prevent graft rejection
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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
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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
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What do CD4+ cells secrete?
IL-2 cytokines are mainly secreted by these cells
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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
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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
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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
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How do CD4+ helper cells activate phagocytes and B lymphocytes?
Actions of PM protein CD40L and secreted cytokines
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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
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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
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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
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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
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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
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