9 - T-Cell Bio Flashcards
What mediates the transcriptional activation of T-lineage genes?
CYTOKINES
NOTCH 1
GATA 3
occurs within the THYMUS
Stem Cell = CLP (Common Lymphoid Progenitor)
VVVV
Pro-T Cell
Bone Marrow
Site of LYMPHOCYTE GENERATION
Hematopoeitic Stem Cell = HSC
common precursor to ALL lymphocytes + other cells
Generative = Primary = Central
LYMPHOID ORGAN
HSC
Hematopoietic Stem Cell
Common Precursor for:
B&T Lymphocytes
dendritic cells / red cells / monocytes / dendritic cells / NK
Pluripotent
single HSC –> generates ALL DIFF TYPES
Self-Renewing = A-symmetric division
What stimulates the PROLIFERATION & MATURATION
of HSC’s?
CYTOKINES
In Bone Marrow
HSC + Cytokines
VVVV
Common Lymphoid Progenitor + Common Myeloid Progenitor
CLP –> Tcells / b cells / Nk cells
CLP
Common Lymphoid Progenitor
In thymus, HSC + Cytokines –> CLP + CMP
CLP
can become T-cells // B-cells / NK Cells
CLP –> THYMUS to MATURE into a T-CELL
Thymus
Primary / Central Lymphoid Organ
CLP migrates to
THYMUS for T-Cell Maturation
Thymocyte = T-lymphocyte within thymus
Cortex –> Medulla
for maturation
Thymus Cortex
OUTER PART
DENSE collection of T-Lymphocytes
Produce IL-7 which is required for
Early T-cell Development
Cortex –> Medulla
for maturation of T-lymphocytes
Thymus Medulla
Cortex -> Medulla
T-Lymphocytes –> MATURE-T-Lymphocytes
Consists mainly of Mature ones
Where this occurs:
Epithelial cells present SELF-ANTIGENS to Developing T-cells
Positive & Negative Selection
Overall Picture of T-Cell Maturation
TCR Structure
- *Heterodimer**
- *2 Disulfide** linked with polypeptide chains
Variable Region = AG binding
Constant = ANCHORs receptor to cell surface
Types of Polypetide chains:
aB TCR = MAJORITY
yG TCR
TCR Genes Features
Once the
- *CLP –> Thymus**
- ALL** of the Genes are THERE, but they are *NOT rearranged yet
Rearrangement by:
Recombinase Enzyme
Significant DIVERSITY in TCR:
VDJGenes withrandom combination
- *TCR DOES NOT SWITCH AFTER IT IS FORMED**
- unlike IG’s*
yG TCR
Only 1-10% of peripheral T-lymhocytes
- *INNATE IMMUNE RESPONSE**
- not Adaptive –>* respond rapidly
- NO memory response*
found in Mucosal epithelial Sites
does NOT bind aB TCR cites = does not bind to MHC
instead they bind to:
Phospholipids / Phospho-AGs / Heat-shock proteins
aB TCR
Expressed on 90% of peripheral T-Lymphocytes
Once COMMITTED to aB –> NO further rearrangements to yG
FXN:
ADAPTIVE Immune response –> Bind to MHC
Shows memory response
ONLY BINDS TO:
MHC1 or MHC2+AG peptide
TCR Complex
Consists of What?
TCR PLUS
2 x CD3 + 2 x ZetaChains
bound by a TIGHT NON-Covalent Association
Do NOT bind the Antigen
Simply:
SIGNAL TRANSDUCTION MOLECULES
Co-Receptors
Transmembrane Glycoprotein Chain
CD4** or **CD8
Bind MHC2 vs MHC1
does NOT bind Antigen!
STABILIZE TCR Complex’s
interaction with the peptide-MHC complex
VVVV
Enhanced T-Cell Activation** & **Signal Transduction
TCR vs BCR
Comparison Chart
3 Stages of T-Cell Maturation
1 = Double Negative
Pro-T-cell –> Pre-T-cell
Express Beta TCR chain only
- *2 = Double Positive**
- *Pre-T Cell** –> Double Positive T-Cell
- *Alpha+Beta TCR** + BOTH CD4/CD8
3 = Single Positive
DP T-Cell –> Mature T-Cell
loses 1 CD chain & matures to either CD4+ or CD8+
Double Negative
Stage 1 of T-Cell Maturation
Pro-T cell
CLP has gotten the SIGNAL = Notch 1 + GATA3, so it is COMMITED
has the TCR genes, but does NOT express TCR complex yet
DECISION is made to be aB TCR OR yG TCR
double negative that fail to express = cell death
B-TCR chain ONLY
IL-7 –> mediates thymocytes proliferation in cortex
RAG1 & RAG2 –> trigger TCR gene rearrangement
IL-7 Function
During Stage 1 of T-Cell Maturation
Mediates the:
Thymocyte Proliferation in CORTEX
vvvvv
Decision to become:
aB TCR or yG TCR
(Pro-Tcell –> Pre-Tcell)
RAG1 & RAG2 Function
Occurs during
BOTH Stage 1/2 of T-Cell maturation
Triggers the:
REARRANGEMENT of TCR GENES
Double Negative Stage 1 –> B TCR chain only
DP Stage 2 –> A TCR also
Double Positive
Stage 2 of T-Cell Maturation
Pre-T Cell –> DP T-cell
- *RAG1/2** trigger the rearrangement
- *A TCR chain** is expressed
BOTH CD4 & CD8
coreceptors are proliferated & expressed
Expression of productive:
TCR Complex + CD4 AND CD8 (Double Positive)
Positive or Negative Selection
occurs at this stage
Single Positive
Stage 3 of T-Cell Maturation
Double Positive T-cell –> Naive T-Cell
Undergoes Phenotypic & functional selection processes:
DP cell will LOSE one CD chain and mature to:
EITHER CD4+ or CD8+
Gains ability to perform their respective functions
- *CD4** –> produce cytokines
- *CD8** –> secrete molecules to kill cells
Migrates to MEDULLA
while undergoing +/- selection via interaction w/ SELF antigen
NAIVE T-Cell
INACTIVE T-cell
DP T-Cell –> Single Positive T-Cell
Cortex –> Medulla
NAIVE until it LEAVES THE THYMUS
to circulate through the lymphatic system
Positive Selection
Occurs when?
Stimulates Survival of T-cells that recognize:
Self Peptide MHC complexes with:
LOW Avidity
(weak recognition)
- *DP T-cell** + MHC1 becomes = CD8 T-cells
- *RUNX** = transcription factor that triggers to LOSS of CD4
DP T-Cell + MHC2 becomes = CD4 T-cells
ThPOK = transcription factor that triggers to LOSS of CD8
Results in a:
SELF-MHC RESTRICTED SINGLE POSITIVE T-CELL
can recognize self, SP t-cell
Death By Neglect
Occurs When
DP T-cell that
does NOT recognize Self-MHC
VVVV
APOTOSIS
ThPOK
- no RUNX*
- *Transcription Factor** that triggers the
- LOSS* of CD8
DP T-cell
VVVVV
CD4+ T-Cell
RUNX
- no ThPOK*
- *Transcription Factor** that triggers the
- LOSS of CD4*
DP T-cell
VVVVV
CD8+ T-Cell
Negative Selection
Occurs when?
Triggers APOPTOSIS of T-cells that:
recognize self-peptide MHC complexes with:
HIGH AVIDITY
Occurs within the cortex & medulla
when DP or SP T-Cells encounter APCs, that display MHC1/2
Eliminates potential of SELF-REACTIVE T-cells
VVV
SELF-TOLERANCE
T-Cell Stages DISTRIBUTION
80% in the DOUBLE POSITIVE stage 2
Most commonly:
CD4+ & CD4+ in the THYMUS
CD4+ T-Helper Cell FUNCTIONS
(or Effector)
66% of T-lymphocytes
Interacts with MHC2
many different types: Th1 / Th2 / Th17 / Treg
Functions:
Help B-Lymphocytes develop into plasma cells
Help Activate CD8+ Cytotoxic T-Cell
Help macrophages effect delayed HYPERsensitivity
Th1 Function
T-Helper Cell CD4+
Th1
Activate CD8+ Cytotoxic T-cells & macrophages
+
initiate delayed HYPERsensitivity reaction
Type of T-Helper cell differentiation is:
made based on signature cytokines secreted
No surface marks differentiate the subsets
Th2 Function
T-Helper Cell CD4+
Th2
Activate B lymphocytes –> plasma cells = IgE Production
Eosinophil Activation
Type of T-Helper cell differentiation is:
made based on signature cytokines secreted
No surface marks differentiate the subsets
Th17 Function
T-Helper Cell CD4+
Th17
Pro-Inflammatory
Type of T-Helper cell differentiation is:
made based on signature cytokines secreted
No surface marks differentiate the subsets
Treg Function
T-Helper Cell CD4+
Treg
Secrete IL-10 & TGF-B
Suppress activity of T/B-cells (other CD4+’s)
SELF-TOLERANCE
involved in auto-reactivity & neg feedback
Type of T-Helper cell differentiation is:
made based on signature cytokines secreted
No surface marks differentiate the subsets
Cytotoxic T-Cell FUNCTION
CD8+ T-Cell
33% of T-cells
interacts with MHC Class 1
Fxns:
- *Elimination of Target Cells:**
- *Virus-infected / Tumor-cells / Foreign Tissue**
Cytotoxic CD8+ T-cells
3 MECHANISMS
- *Cytotoxic Granule Proteins**
- *Perforin** –> holes -> apoptosis
Toxic Cytokines
IFN-y & TNF-A
interact w/ receptor –> apoptosis
Cell Surface Molecule Interaction
FasL - Fas
Fas on cell –> death dopain -> caspase-3
Toxic Cytokines
1 of 3 CD8+ T-Cell Mechanisms
IFN-y** & **TNF-a
Released directly onto target cell surface
VVVV
interect w/ receptor
VVVV
APOPTOSIS
Cytotoxic Granule Proteins
1 of 3 CD8+ T-Cell Mechanisms
PERFORIN
Engages target cell
VVVV
lysosomal structures –> release Perforin
VVVVV
forms PORES in membrane
VVVVV
Apoptosis
Cell Surface Molecule Interaction
1 of 3 CD8+ T-Cell Mechanisms
FasL - Fas
Engages Fas on target cell
VVVV
Triggers intracellular “death” domain
V
activates Caspase -3
V
APOPTOSIS
