1
Q
Innate immune response turns on the adaptive immune response to due interaction at dendritic cell- t cell synapse
A
2
Q
T cell receptor
A
- Heterodimer with 2 transmembrane glycoprotein chains (alpha and beta)
- The extracellular portion of each
chain consists of two domains,
resembling Ig V and C domains - Very short cytoplasmic tail - needs other proteins to transduce signals
3
Q
CD4+ T cells
A
help to orchestrate the immune response in an antigen specific fashion
Helper T cell
4
Q
CD8+ T cells
A
cells eliminate host cells that
are infected with intracellular parasites
and/or viruses that are beyond the
reach of antibodies. The “yin” to the B-cell’s “yang”
5
Q
Cellular Immunity
A
mediated by T cells. Responds to intracellular infection.
6
Q
Humoral Immunity
A
mediated by B-cells and the antibodies they produce. Responds to extracellular infection.
7
Q
Revisit VDJ recombination slides (11-13)
A
number of V and J regions each person has on their chromosomes is different
8
Q
Naive T cells require 3 signals for activation and what kind of cell can provide all 3
A
- Only a “professional” APC can provide all signals for T cell activation. - This requirement limits autoreactivity.
1. TCR - MHC with peptide
2. Costimulation (cell surface molecules upregulated by APCs when they see immunologic danger)
3. Cyotkines
9
Q
TCR Signaling is associated with … and initiated by…
A
- TCRs have no signaling domains of their own
- TCR is always associated with the adaptor complex CD3
- CD3 has 6 chains
- Signaling is initiated by phosphorylation of immunoreceptor tyrosine-cased activation motifs ITAMs) on CD3
10
Q
Initiation of TCR Signaling
A
- CD4/CD8 is attached to the initiating kinase (Lck) - bring the kinase to all the CD3 chains
- Zap-70 is another kinase - eventually results downstream phosphorylation/activation of PLC-gamma (point of no return)
11
Q
Costimulatory Signaling (signal 2)
A
- B7 on the APC binds CD28 on the T cell
- leads to a signaling cascade that results in a 2nd hit on PLC-gamma
- PLC gamma activates Calcium signaling-> activates NFAT, Ras/MAP kinase-> activates AP-1, NFkB - not sure if this is correct
- All these are transcription factors that goes to the nucleus
12
Q
Cytokine signaling (signal 3)
A
- rapid signal to the nucleus tells you how fast T cell will proliferate and its fate
13
Q
T cell recognition of peptide-MHC complex
A
- TCR INDIRECTLY recognizes peptide through the MHC
14
Q
MHC 1 vs MHC 2 in terms of what they present
A
- MHC1 presents endogenous peptides to CD8 T cells
- MHC2 presents exogenous peptides to CD4 T cells
- peptides are bound tightly to the MHC
15
Q
MHC Class 1 molecule structure and what cells express them
A
- Alpha chain has 3 domains
- alpha 1 and alpha 2 create a peptide binding cleft
- alpha 3 binds beta2-microglobulin
- peptides are 8-10 amino acids long
- the peptide binding cleft is closed - which prevents larger peptides from binding
- Expressed by all NUCLEATED cells (ex: not RBCs) - it is how they are surveilled by NK cells (all nucleated cells do this so that internal contents can be reviewed by the immune system)
16
Q
MHC Class 2 molecule structure and what cells express them
A
- Has 2 transmembrane chains
- alpha 1 and beta 1 create a peptide binding cleft (that is open as opposed to being closed like in MHC 1)
- peptides 13 -17 amino acids long bind, longer peptides can be bind but can also be trimmed at the ends
- expressed constitutively on professional APCs (DCs, Macrophages, B cells, and microglia of the CNS)
16
Q
MHC locus
A
You have 3 MHC loci from each parent - what does this mean?
17
Q
Human MHC nomenclature
A
- HLA (human leukocyte antigen)
- class 1: A, B, and C
- class 2: DR, DP, DQ - both alpha and beta loci exhibiting far great polymorphism
18
Q
Mouse MHC nomenclature
A
H-2 (linked to antigen 2)
- class 1: K, D, L
- class 2: A, E, M, O
- alleles designated by superscripts
19
Q
Polymorphism
A
- Variation at a particular locus
19
Q
Full MHC nomenclature
A
Species - Gene Locus *Major Allele historically identified by serology:Minor allele variant typically identifiable only by PCR
20
Q
Why is it important that MHC genes are very polymorphic
A
- High MHC polymorphism ensure that there will always be some individuals in a population that can present a particular antigenic epitope
- Codominant expression ensures that many peptides will be presented by each person
21
Q
Alleles
A
variants occupying the locus
22
Q
Allelic variation occurs in what part of the MHC
A
the peptide binding cleft
23
review AIDS and cancer slide
- more diverse hla alleles means you can present many more peptides of the same pathogen - harder for the pathogen to evolve around the immune system
24
MHC 2-restricted presentation by Dendritic cells
- Ingest antigen, migrate to LNs, become less phagocytic, stabilize MHC class 2, and upregulate costimulatory activity
25
MHC 2-restricted presentation by macrophages
- Inducible class 2 and costimulatory activity by bacteria through PRR
26
Professional antigen presenting cells
Dendritic Cells, Macrophages and B cells
27
Generation of class 1 restricted peptides
Proteins unfold and pass through the Proteosome, where they are degraded by trypsin like (basic) and chymotrypsin-like (hydrophobic) activities
28
Mechanisms of antigen uptake
- Phagocytosis
- Pinocytosis
- Receptor Mediated Endocytosis (overlaps with phagocytosis)
29
Generation of class 2 restricted peptides
1. Antigens are taken up by professional APCs (DCs, Macrophages, B cells) into intracellular vesicles
2. In early endosomes of neutral pH, endosomal proteases are inactive
3. Acidification of vesicles activates proteases (especially cathepsin S, L) to degrade antigen into peptide fragments
4. Vesicles containing peptides fuse with vesicles containing MHC Class 2 molecules
30
____ leads to DC expression of signal 2 and 3 in T cell signaling
Danger signals (PAMPS)
31
Cytosolic Pathogens
- Presented by:
- Degraded in:
- Peptides bind to:
- Presented to:
- Effect on Presenting cell:
- Presented by: Any cell
- Degraded in: Cytosol
- Peptides bind to: MHC class 1
- Presented to: CD8 T cells
- Effect on Presenting cell: Cell Death
32
Intravesicular Pathogens
- Presented by:
- Degraded in:
- Peptides bind to:
- Presented to:
- Effect on Presenting cell:
- Presented by: Macrophage
- Degraded in: Endocytic vesicles (low pH)
- Peptides bind to: MHC class 2
- Presented to: CD4 T cells
- Effect on Presenting cell: Activation to kill intravesicular bacteria and parasites
33
Extracellular Pathogens and Toxins
- Presented by:
- Degraded in:
- Peptides bind to:
- Presented to:
- Effect on Presenting cell:
- Presented by: B cells and all professional APCs
- Degraded in: Endocytic vesicles (low pH)
- Peptides bind to: MHC class 2
- Presented to: CD4 T cells
- Effect on Presenting cell: Activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins
34
What cytokine increases expression levels of MHC class 2
IFN-gamma
-Most cells can/will upregulate MHC class 2 expression in response to interferon signaling
35
MHC 2-restricted presentation by B cells
- Not phagocytic but endocytose bound protein
- Costimulatory activity can be induced by bacterial constituents (e.g. LPS) through PRR
- Constitutively express MHC class 2
36
Dendritic cells
- Antigen uptake:
- MHC expression:
- Costimulatory activity:
- Antigen presented:
- Location:
- Antigen uptake: macropinocytosis, phagocytosis, and viral infection
- MHC expression: Low on tissue DCs but high on DCs in lymphoid tissues
- Costimulatory activity: Constitutive by mature non phagocytic lymphoid dendritic cells (++++)
- Antigen presented: Peptides, Viral Antigens, Allergens
- Location: Lymphoid Tissue, Connective Tissue, Epithelia
37
Macrophages
- Antigen uptake:
- MHC expression:
- Costimulatory activity:
- Antigen presented:
- Location:
- Antigen uptake: Phagocytosis
- MHC expression: Inducible by bacteria and cytokines
- Costimulatory activity: Inducible from - to +++
- Antigen presented: Particulate antigens, intracellular and extracellular pathogens
- Location: Lymphoid and connective tissues, body cavities
38
B Cells
- Antigen uptake:
- MHC expression:
- Costimulatory activity:
- Antigen presented:
- Location:
- Antigen uptake: Antigen-specific receptor (Ig)
- MHC expression: Constitutive, increase on activation
- Costimulatory activity: Inducible - to +++
- Antigen presented: Soluble antigens, Toxins, viruses
- Location: Lymphoid tissue and peripheral blood
39
Pinocytosis
uptake of small solute molecules by membrane invagination
40
Receptor mediated endocytosis
Internalization of viruses and bacteria bound to cell-surface receptors
- Antibody coated pathogens can be internalized by Fc receptors
- Invariant structures on bacteria (e.g. LPS, high mannose sugars) can be internalized by distinct receptors
- BCR can internalize bound protein
- overlaps with phagocytosis
41
Loading of peptide onto class 2 molecules
1. Invariant chain (li) called CLIP binds to MHC class 2, blocking the binding of peptides and misfolded proteins (in the endosome)
2. li is cleaved in an acidified endosome just leaving CLIP bound to MHC class 2
3. Endocytosed antigens are degraded to peptides in endosomes, but the CLIP peptide blocks their binding to MHC Class 2
4. HLA-DM binds to MHC Class 2, releasing CLIP and allowing other peptides to bind. (HLA-DM is negatively regulated by HLA-DO)
5. MCH Class 2 molecules travels to the surface
42
TAP transporter
- member of the ATP binding cassette (ABC) transporter family
- passes peptides from the cytosol into the ER (it is a transmembrane protein in the ER)
43
Class 1 Peptide presentation
1. Partially folded MHC class1 alpha chains bind to calnexin until beta2-microglobulin binds (this all occurs on the ER membrane)
2. MHC class 1 alpha:B2m complex is released from calnexin, binds a complex of chaperone proteins (calreticulin, Erp57) and binds to TAP via tapasin
3. Proteasome degrades cytosolic protein into peptide fragments
4. TAP translocates 8-12 aa peptides from cytosol to ER, where empty MHC 1 are loaded and complete their folding
5. Fully folded MCH class 1 molecule is released from the TAP complex and exported
(stuff that goes to the surface is a mix of class 1 and 2)
44
Class 1 MHC molecules cannot leave the ER unless...
stabilized by a bound peptide
45
Purpose of MHC-1 vs 2
1: to kill infected cells
2: to activate other immune cells
GS-IY-6200
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