1
Q
Clonal Selection Theory - 4 Basic Principles - know the figure that goes along with this slide
A
1) Each nascent lymphocyte generates a single receptor
with unique specificity.
2) Lymphocytes bearing receptors that are self-reactive
are deleted during development.
3) Binding of the receptor to its specific antigen ligand
causes activation of the lymphocyte and when antigen is
eliminated, the immune response ceases.
4) Lymphocyte activation results in the expansion that cell
forming a clonal population of effector cells each bearing
the identical receptor as the parent.
know the figure that goes along with this slide
2
Q
Tolerance
A
Not mounting an immune response to inappropriate stimuli
3
Q
Central Tolerance
A
- It is a mechanism aimed at eliminating T cells with reactivity to healthy tissues during thymic development
- Hallmark: CLONAL DELETION, suicide of immature T cells with high -affinity for self-antigens
4
Q
Peripheral Tolerance
A
- Other mechanisms to ensure self-tolerance are peripheral (e.g. anergy, suppressive APC, Tregs)
- Gets rid of stuff that got through the central tolerance process
- T cells that get past the thymus will interact with non-APC first and become anergic.
- They can also interact with non-activated (partially mature) DCs.
- Tregs created in the Thymus and in the periphery can suppress auto-reactive effector T cells
5
Q
Cellular Organization of the Thymus
A
- Bone-marrow derived early thymic progenitors (ETPs) enter via HEV (High endothelial Venules)
- medullary and cortical epithelial cells
- Dendritic cells, macrophages, and B cells come in from the periphery
6
Q
role of cTECs
A
- Positive selection
- select for TCRs that can recognize MHC at all
7
Q
role of mTECs
A
- Negative selection
- mTECs express all kinds of self peptides, and APCs bring them from the periphery
8
Q
AIRE - Autoimmune Regulator
A
- Transcription complex expressed by mTECs
- makes sure all proteins and peptides in the genome are expressed
- Drives expression of peripheral tissue antigens
9
Q
Natural T regs
A
- right on the border of binding too tightly or not enough to MHCs, so they are retained during selection of T cells
- they will control immune responses
10
Q
CD4 vs CD8 is determined by
A
How much time the T cells spend with MHC 1 vs 2, after that it is given signals to upregulate CD8 vs CD4
11
Q
Somatic cells much more
resistant to radiation
damage than hematopoietic
cells from the bone marrow
A
12
Q
DANGER signals (adjuvants, PAMPs etc.) lead to DC expression of …
A
Costimulation and cytokines -> activated T cell
It also enhances signal 1 by increasing MHC expression
13
Q
Pathogens trigger migration of DCs to secondary lymphoid organs because
A
- lymph nodes are where immune responses against pathogens occur, where the T cells and dendritic cells meet up
- Pathogens will also trigger DCs to upregulate cytokines and costimulatory receptors (B7 that binds to CD28)
14
Q
Lymph node organization
A
- has both blood and lymphatic supply
- B cells on the outside (germinal center)
- T cells in the middle
- Dendritic cells on the innermost layer
15
Q
How T cells enter and exit the lymphatic system
A
- T cells enter the lymph node cortex from the blood via high endothelial venules (HEVs)
- T cells not activated by antigen presented DCs exit the lymph node via the cortical sinuses
- T cells activated by dendritic cells start to proliferate and lose the ability to exit the lymph node
- Activated T cells differentiate to effector cells and exit the lymph node
- S1PR1 is upregulated once dendritic cell is done, allowing t cell to leave
16
Q
_____ dictate DCs migration and antigen presentation
A
TLRs and pathogens
17
Q
CCR7
A
- expression is induced TLR signaling
- Directs migration into lymphoid tissues by allowing DCs to bind to cells that have CCL 19 and CCL 21
- Augments expression of co-stimulatory and MHC molecules
18
Q
DC activation via TLRs leads to:
A
o chemokine receptor changes
o trafficking from tissue to LN
o increase in MHC expression
o increase in co-stimulatory molecule
expression (B7.1 and B7.2)
o decrease in antigen processing
o stability of MHC/peptide cell surface
complexes - 1/2 life of class 2 goes from 4 hours to 4 days almost once DCs gets danger signal
19
Q
Immunological synapse organization
A
- outer ring (pSMAC): non-specific stick molecules
- inner ring (cSMAC): where the specific interaction is, CD28, MHC etc.
20
Q
Th1 response
A
intracellular pathogens
21
Q
Th17
A
- layered on top of TH1 and TH 2
- calls in neutrophils - to kill in a non-specific way
22
Q
Th2
A
- eukaryotic pathogens
23
Q
Treg
A
- T cells become anergic, can no longer respond to immunologic danger
24
Q
Cytokines Signal via JAK/STAT
A
- Dimerization via cytokine binding
- Activation of cytoplasmic JAKs by cross-tyrosine phosphorylation
- Receptor is tyrosine phosphorylated to generate SH2-binding domain
- STAT (transcription factor) recruitment (to the phosphorylated receptors)
- STAT activation by carboxy-terminal tyrosine phosphorylation by JAKs
- STAT dimerization via SH2 domains
- Nuclear translocation of STAT dimers
- Gene expression (or repression)
25
Important JAK/STAT signaling characteristics
- Produce immediate responses
- Cause rapid changes in nuclear gene expression
- Can elicit very different effects on different target cells
- Can exhibit functional redundancy on the same cell type
- Receptors are typically heterodimeric with common sharing subunits
- Signaling occurs through Janus kinase phosphorylation of Signal Transducer and Activators of Transcription (STATs)
26
Process of CD4 T cell
CD4 T cells that recognize related antigens presented by the antigen-presenting cell can amplify the activation of naive CD8 T cells by further activating the antigen-presenting cell
- B7 expressed by the dendritic cell first activates the CD4 T cells to express IL-2 and CD40 ligand
- CD40 ligand binds CD40 on the dendritic cell, delivering an additional signal that increases the expression of B7 and 4-1BBL by the dendritic cell, which in turn provides additional co-stimulation to the naive CD8 T cell.
- The IL-2 produced by activated
CD4 T cells also acts to promote effector CD8 T-cell differentiation.
27
CD8 T cells- cytotoxic lymphocytes and how they kill other cells
- primary function is to kill infected cells
- recognize antigen on MHC class 1
- MHC class I is expressed on all tissues of the body; therefore, if any tissues are infected, CD8 killer T cellscan kill the infected cells.
- Most killing by CTL’s require contact between CTL and its target cell
- Utilize perforin/granzyme delivered in lytic
granules or FasL expressed on CTL cell surface
- Perforin makes holes in cell membrane, granzyme is then delivered and induces apoptosis (initiates Caspase cascade)
- Fas ligand (FasL) binds to Fas on infected cells and induces apoptosis - not the primary way stuff gets killed
28
Thymus is essential for
T cell development
29
Immature T cells are called
thymocytes
30
Roles of Thymic DCs and B cells during T cell development
Thymic DCs:
- Take up tissue restricted antigens
- Promote development of regulatory cells
- Mediate negative selection
Thymic B cells play a similar role
31
What is the most important mechanism of T cell central tolerance
clonal deletion of self-reactive T cells
32
Most high affinity TCRs are deleted by some are selected as...
Regulatory T cells to control immune responses
33
Positive selection in the cortex of the thymus
Thymocytes able to recognize SELF-peptide on SELF-MHC are rescued from cell death.
34
Is TCR/MHC signaling enough to activate a T cell?
NO, it requires 3 signals
35
3 important transcription factors of T cell signaling
1. NFAT
2. NFkB
3. MAPK cascade that activates a component of the AP-1 transcription factor
36
DANGER signals from PAMPs upregulate (s
B7
37
Interaction between Mature DCs that enter the lymph node and resident DCs there
They can transfer some antigens to resident DCs
38
CD4 Th1 cells
- Important against intracellular infection (and some extracellular bacteria)
- Signal 3: IL-12 and IFN-gamma
- Master Transcriptional Regulator: T-bet
- Act primarily by secret of IFN-gamma (but also secrete TNF-a and IL-2)
- IFN-gamma + CD40 ligand can activate macrophages to kill bacteria
- IL-2 can boost NK cells, enhancing their killing capacity
- Th1 cytokines instruct the innate and adaptive systems to produce cells and antibodies against both viruses and bacteria
39
CD4 Th2 cells (Signal 3 and master transcriptional regulator)
- Important against eukaryotic infection
- Signal 3: IL-4
- Master Transcriptional Regulator: GATA-3
- Primarily acts through secretion of IL-4, IL-5 and IL-13
- These cytokines help B cells switch isotypes of their IGs to those appropriate for fighting eukaryotes (IgE)
- IgE binds receptors on basophils and eosinophils, activating them
40
CD4 Th17 cells
- Primary role is to recruit neutrophils to the site of infection IL-17 which acts through IL-17 receptors expressed on epithelial and endothelial cells.
- These then secrete chemokines and increase vascular permeability to recruit neutrophils
- Important for protection against extracellular bacteria and fungal infections
- Signal 3: TGF-beta and IL-6
- Master Transcriptional Regulator: ROR-gamma-T
- They also secrete IL-6
41
Loss of function in IL-17R or lack of IL-17 production leads to
chronic fungal infections
42
Signal 3 and master transcriptional regulator for Treg cells, also what cytokines they secrete
Signal 3: TGF-beta
- Master Transcriptional Regulator: FoxP3
- Secretes: TGF-beta, IL-10
43
CTLA-4
- upregulation attenuates the T-cell response (another level of peripheral tolerance)
- is expressed on the surface of activated effector T cells and T regs.
- resembles CD28 but binds with 20-100x greater affinity and provides an inhibitory signal dampening T cell activation
44
How do Alloreactive T-cells generally react with MHC
in a peptide independent fashion
GS-IY-6200
flashcards
Decks in class (8)
# Cards
