10 - T-Cell Flashcards
What is found on EVERY surface of
B-Cells / T-cells / pancreatic Cells
MHC1 Molecules
What type of Lymphocyte?
Mature lymphocyte that resides in lymph nodes
Fxn = Ag Recognition, has NOT encountered AG yet
T-Cell
protein Ag ONLY // require Ag Presentation
B-Cell
any organic molecule // can recognize Ag on their own
NAIVE LYMPHOCYTE
What type of LYMPHOCYTE?
Activated lymphocyte that performs functions to
ELIMINATE MICROBES
in the Periphery
EFFECTOR LYMPHOCYTES
What type of LYMPHOCYTE?
Long-Lived // Functionally SILENT
Mount a RAPID response to Ag challenge
secondary response
MEMORY LYMPHOCYTES
Phenotypically different:
Express a HIGH LEVEL of:
INTEGRINS // CHemokine Receptors
MHC General Functions
Control POSITIVE / NEGATIVE SELECTION
Present Protein-Ag to T-Lymphocytes
MHC Class 1
Expressed on what?
Gets Antigen from where?
Expressed by:
nearly ALL NUCLEATED CELLS
and interacts with CD8+ Cytotoxic T-cells
- *INTERNAL Defect Alert**
- *EndoGenous** protein Ag is catobilized in the CYTOPLASM
Good for detecting:
VIRUS / CANCER
MHC Class 2
Expressed on what?
Gets Antigen from where?
Expressed on:
SPECIALIZED APCs
and interact with CD4+ Helper T-cells
- *EXTERNAL Problem Alert**
- *EXOgenous protein Ag** catabolized in ACID DEPARTMENT
APC Functions
Process & Present Ag –> T-cells
Provide Secondary Stimuli to the T-cell, required for:
achievement of Full-Tcell response
Nearly ALL nucleated cells express MHC1
for interaction with CD8+ Cytotoxic T-cells
These Express MHC2 proteins for CD4T-cells, but ALSO MHC1
Dendritic > Macrophages > B-cells
Which APC is this?
Most efficient in INITIATING the Adaptive immune response
Travel from periphery (site of infxn) –> lymph nodes
to activate Naive T-cells
Have the broadest range of Ag presentation
high levels of these molecules:
MHC + Costimulatory + Adhesion
DENDRITIC CELLS
initiate the adaptive immune response
Which APC is this?
Provide CONTINUOUS stimuli to keep T-cells going
Located in the periphery (site of infection)
Baseline MHC2 is low
VVVVVV
Cytokine stimulation –> MHC2 increase
MACROPHAGES
Which APC is this?
Have high affinity for Ag & rapidly process AG onto MHC
important for
Immunologic Recall
or
Later on during primary infection
B-Cells
Phases of Adaptive Response
Lymph Nodes
Lymph Nodes
Collection points where APCs interact with NAIVE T-Cells
dendritic cell –> 500 t-cells/hr, 8-10 hours after exposure
APC-MHC-Ag interacts with the Specific TCR complex
on T-cell
VVVV
CD4 = Coreceptor that:
Stabilizes Interaction & Enhances Signaling Potential
but this is NOT ENOUGH FOR ACTIVATION
Why is
Contact between TCR & APC
NOT SUFFICIENT
in Fully Activating T-Cells?
Few IDENTICAL MHC/Ag complexes
on surface of 1 APC
*Low AFFINITY* of interaction
cells are always moving / dissociating
SHORT Cytoplasmic Tails
CD3 / Zeta molecules with TCR are not strong enough to propagate the AG signal
What is required for FULL T-cell Activation?
Naive T-Cell –> Effector T-cell
TCR-APC-Ag
Complexing / contact, required but NOT SUFFICIENT
- *Co-Receptor**
- *CD4** or CD8
CoStimulatory Pairs
B7-CD28 // CD40-CD40L
ESSENTIAL
ADHESION MOLECULES
Stabilize T-cell + APC contact
Assist in migration of T-cell –> site of inflammation+infxn
Costimulatory Pairs
Types
Function
B7 + CD28
CD40 + CD40L
ESSENTIAL for activation of Naive T-cells
Inhibition of this pair binding –> IMPAIRED t-cell response
how we KNOW this is needed for activation
Effector / Memory T-cells require LESS costimulation
vs NAIVE T-cell
B7 - CD28
Costimulatory Pairs necessary for Naive T-cell maturation
Fxns:
Mobilizes kinases around TCR
Increases HALF LIFE of cytokine mRNA
Increases T-Cell Proliferation
PREVENTS induction of Anergy & Cell death
induces expressio of ANTI-apoptotic proteins
CD40 / CD40L
Costimulatory Pairs
On APC:
Promote UP-Regulation of MHC + other costim molecueles
&
Promotes LONGEVITY of Dendritic cell by
increasing IL2 production
Important for B-cell Activation, promotes:
B-cell proliferation // Ig Class switching
Adhesion Molecules
NOT specific to T-cells or APC
- *TCR-Ag engagement
- ->**UPREGULATE expression of Adhesion molecules
These form an outer ring,
STABILIZING T-Cell + APC contact
and assist in the MIGRATION of t-cells –> inflammation/infxn site
- *LFA-1 Integrin + CD54**
- *LFA-3 Integrin + CD2**
ZAP-70
- *KINASE** involved in T-cell+APC SIGNAL TRANSDUCTION
- absense of ZAP-70 –> severe immunodeficiency*
PLC-y activation -> PIP1 -> IP3 -> ^Ca2+^
VV
CALCINEURIN (enzyme)
there is also PKC // ERK+JNK
VV
NFAT (transcription factor)
V
IL-2 Cytokine Production
most important cytokine signal for Proliferation / more Receptors
CALCINEURIN
ENZYME that activates NFAT
NFAT = transcription factor
that produces IL-2
which is the most important CYTOKINE SIGNAL
for proliferation // self-promoting // more receptors
- *Three Signals Needed for**
- *T-Cell Proliferation & Differentiation**
#1 Antigenic Signal
TCR+MHC2-Ag
#2 Costimulatory Signal
Costim Pairs = B7/CD28 + CD40/CD40L
Adhesion Molecules
#3 Cytokine Signal
ZAP-70 -> Calcineurin -> NFAT -> IL-2 Production
Proliferation
of Naive T-cell
After the 3 signals, the T-cell secretes its own:
IL-2 = Growth Promoting Cytokine
&
Expresses Cell surface receptor for that Cytokine (IL2 receptor)
Obey the principle of clonal expansion:
Active cell PROLIFERATES to build up clones w/ same Ag specificity
T-cell doubles its # q6 hours for 3-4 days
VVV
DIFFERENTIATION occurs
What happens after T-cell Activation ENDS?
APC - Naive T-cell –> DISENGAGE
APC goes on to activate other Naive T-cells
Activated T-cell:
DOWN REGULATES expression of homing molecules
&
Up Regulates expression of
chemokine receptors + adhesion molecules
allowing it to migrate OUT of lymph node –> affected tissue
Differentiation of T-cell after Activation
Occurs after proliferation
Active CD8+ Tcytotoxic cells –> destroy Ag carrying cells
Active CD4+ Thelper cells –> secrete Cytokines
how does it know what cytokines?
Presence of current cytokines at the time of Ag-recognition
holds a key to T-cell differentiation
LIneage-Determining txn factors
- *Th1**
- *Differentiation / Secreted Cytokines / Function**
Naive CD4 + IL-12 (dendritic cell) –> Th1
Secretes:
INF-y** & **IL-2
- *CELLULAR RESPONSES**
- *Anti-viral/microbial activity**
Cell-mediated Immunity
Inflammation
Th2
Differentiation / Secreted Cytokines / Function
Naive T-cell + IL-4 (mast cell)–> Th2
stay in lymph nodes to activate B-cells
Secretes:
IL-4 / IL-5** / **IL-13
- *ANTIBODy / HUMORAL (b-cell) RESPONSE**
- *immunity to EXTRAcellular parasites**
ALLERGENS
IgE / IgA / Eosinophil Recruitment / Mast-cell Recruitment
INF-y
Which T-cell secretes this & What does it act on/fxn
Dendritic Cell –> IL-12 –>
Th-1
INF-y acts on Activated Macrophages
for
Cell-Mediated Immunity
Phagocytosis / Cytotoxicity
CD8- Tcytotoxic Cell Activation
can NOT directly recognize Ag
VVV
Ag must be processed & presented on MHC1 molecule
VVV
CD8+ cell Recognizes a SPECIFIC MHC-Ag combination
2 activation pathways:
CD4+ Th INDEPENDENT
CD4+ Th Dependent
CD4+ Th INDEPENDENT activation pathway
CD8+ Tc Cell Activation
- *DIRECT interaction** w/ MHC1 presenting cell
- *APC** or virus infected cell
Activation & proliferation of CD8+ Tcells
capable of killing cells that express the activating Ag MHC1
transplant rejection:
CD8+ cell recognizes non-self MHC1 on tissue or dendritic cells
- *CD4+ Th Dependent Activation Pathway**
- *CD8+ Tc Cell ACtivation**
APC/CD4+ interaction produces CYTOKINES (IL-2)
VVV
Induces CD8+ Tc cell activation
VVV
Destruction of target cells w/ MHC1 associated Ag Peptides
CD8+ Activation REQUIRES:
- *Tc recognizes a COMBO of Ag + MHC**
- rather than the Ag alone*
- *Same MHC1 Protein**
- *HLA-A** or B or C
Same Ag Epitope
CD8+ Cytotoxic T-cell
KILLING MECHANISMS
Perforin -> Granzymes (cytotoxins)
Granzyme B can activate initiator caspases
Fas/FasL** –> **CAPSPASE
CASPASES
CD8+ Cytotoxic T-cell Killing Mechanism
Present initially as Procaspase = Zymogen
NO ACTIVITY until cleaved or activated by:
Granzyme B
activates Initiator Caspases –> effector/excutionor caspsases
- *Death Receptor = Fas**
- *directly activate initiator caspases**
VVV
Activation of apoptosis and death of virally infected cell
Production of
CD8+ Memory T-cells
After pathogen clearance, the immune response is:
Self-Limiting & most cells die
leaving a
small # of Memory CD8+ T-cells
that are
ONLY generated via Th-DEPENDENT activation
needs the T-helper to activate it
Negative signals from CTLA4 via B7 Protein
Functions of
CD8+ Memory T-cells
PRODUCED RAPIDLY
Require LESS COSTIMULATION
vs naive cells, activated w/ less antigen
produce GREATER # of CYTOKINES
vs naive cells
Negative Regulation
Prevents HYPER-activation of immune response
Achived by Negative Signals from:
CTLA4** via **B7 protein
that serves as a
natural inhibitor & leads to memory Cell generation
within 24-48 hours
deregulation of T-cell fxn –> immunodeficiency / Autoimmunity
CTLA4
CTLA4 via B7 Protein binding serves as a:
NATURAL INHIBITOR of T-cells
&
Leads to MEMORY CELL generation
Necessary for preventing HYPER-activation of immune response:
NEGATIVE REGULATION
- *B7** normally binds CD28 –> to activate T-cell
- *CTLA4 production is UP-REGULATED after this**
