Ch. 9 T-Cell Development Flashcards
Where does T cell development begin in the body?
very early thymocyte development starts in the bone marrow
Which cytokine is critical for developming HSCs into CLPs?
The cytokine IL-7 is critical for transitioning hematopoietic stem cells (HSCs) into common lymphoid progenitors (CLPs)
Which receptor leads CLPs to the thymus?
Some undifferentiated thymocytes begin to express the receptor CD44 which is an adhesion molecule that allows cells to home to the thymus.
Which ligand is critical for developing CLPs into TNKs?
notch ligand signaling
CD44
an adhesion molecule (homing to the thymus)
C-kit (CD117)
receptor for stem cell growth factor (keep undifferentiated cells alive)
CD25
the a chain of the IL-2 receptor (important in key stages of T cell development)
DN1
c-kit(CD117)++, CD44+, CD25-
DN2
c-kit++, CD44+, CD25+
DN3
c-kit+, CD44-, CD25+
DN4
c-kit low/-, CD44-, CD25-
Where does DN1 occur?
bone marrow to thymus
Where does DN2 occur?
subcapsular cortex
Where does DN3 occur?
subcapsular cortex
Where does DN4 occur?
subcapsular cortex to cortex
What is the outcome of pre-TCR signaling?
- Suppression of further rearrangement of TCR β-chain & γ/δ-chain genes, resulting in allelic exclusion
- Rapid proliferation in the subcapsular cortex
- Cessation of proliferation
- Initiation of TCRα chain rearrangement
- Maturation to the DN4 stage (c-kitlow/−CD44−CD25−)
Why does proliferation following pre-TCR signaling lead to increased binding diversity of T cells?
Because cells proliferate after successful β-chain rearrangement, & then stop alterations prior to making TCRα chain, we get a population of cells with the same β-chain & different α chains BINDING DIVERSITY
Function of αβ T cells
αβ T cells are the dominant participants in adaptive immunity & are primary found in SLOs
Function of γδ T cells
γδ T cells are less understood, but appear to bridge adaptive & innate immunity & show up more in peripheral tissues
Why are αβ T cells more common than γδ T cells (based on recombination successes)?
• To become an αβ T cell, only relies on successfully rearranging the β loci to form pre-TCR (and shut down rearrangement of γ & δ)
• To become a γδ cell, cell must successfully rearrange BOTH genes & produce two functional proteins
o Because of this, TCRαβ outcomes are more likely than TCRγδ
On average, what percentage of T cells circulating in peripheral blood are γδ T cells?
5%
Do γδ T cells progress to the DN4 stage of development? Why or why not?
No, Additionally, γδ only go through early thymocyte development, & leave the thymus after the DN2 or DN3 stage (when their TCR is rearranged)
What goals have been accomplished at the end of early thymocyte development?
- Hematopoietic cell precursors have expanded in the subcapsular cortex
- Cells have committed to the T-cell lineage
- Cells have “chosen” to become TCR-αβ or TCR-γδ T cells by recombining their TCR gene loci
- TCR-γδ T cells have left the thymus & begin circulating
- TCR-αβ cells express both CD4 & CD8 (DP cells)
What is positive selection & what is the result for T cells of this selection process?
Positive selection selects thymocytes bearing moderate-affinity receptors capable of binding self-MC molecules, resulting in MHC restriction.
What is negative selection & what is the result for T cells of this selection process?
Negative selection selects against thymocytes bearing high-affinity receptors for self-MHC/peptide complexes, resulting in self-tolerance.
Positive selection is mediated by ________ cells in the thymic cortex.
cortical thymic epithelial cells
___% of cells fail selection in the cortex.
95-98%
What are the four possible outcomes of T cell selection in the cortex?
- TCRs can’t bind; cells die by neglect
- TCRs bind too strongly; negative selection (deletion) occurs
- TCRs bind “just right”; positive selection to single-positive stage occurs
- TCRs bind slightly more, making TREG cells
What determines whether a DP T cell will develop into a CD4+ TH cell or a CD8+ TC cell?
TCR binding to MHC II, also binds with CD4, selecting the cell to the CD4+ subset
◦ TH cells
The opposite happens if TCR binds MHC I, selecting the CD8+ subset
◦ TC cells
Another round of negative selection is mediated by ________ cells in the thymic medulla.
Medullary thymic epithelial cells (mTECs)
What is the purpose of AIRE expression in thymic epithelial cells?
Autoimmune regulator protein (AIRE) induces expression of many tissue-specific proteins in medullary thymic epithelial cells (mTECs)
Dendritic cells also participate in negative selection in the medulla of the thymus. How are they able to do this?
Medullary dendritic cells can acquire mTEC antigens by engulfing mTECs and also participate in negative selection
What is the end result of negative selection in the thymus?
Ensures self-tolerance
Upregulation of the transcription factor ______ leads to three major outcomes that leads T cells towards the circulatory system and SLOs and keeps the cells alive.
Foxo1
What genes are upregulated by Foxo1 ?
- Sphingosine-1-phosphate receptor
- IL-7R
- CCR7
Sphingosine-1-phosphate receptor (S1PR)
required to help T cells travel to the circulatory system and inflamed tissues
IL-7R
gives survival signals to mature T cells (cytokine)
CCR7
a chemokine receptor that helps cells exit and traffic to lymph nodes
What are RTEs?
RTEs= recent thymic emigrants
How does RTE activation compare to mature, naïve T cells?
o Not as functionally mature as older cells
o Don’t proliferate or secrete cytokines as vigorously in response to TCR stimulation
o An area of active research, but it appears that interactions in SLOs leads to maturation of RTEs to mature, naïve T cells in about 3 weeks
About how long does it take for an RTE to mature into a fully functional naïve T cell?
about 3 weeks
How do Treg cells inhibit adaptive immune responses?
- Deplete the local area of stimulating cytokines
- Produce inhibiting cytokines
- Inhibit APC activity (inhibit their maturation)
- Directly kill T cells
What transcription factor is upregulated in T cells to make the TREG cells?
FoxP3
How is tolerance maintained in the periphery for cells that escape negative selection in the thymus?
Peripheral mechanisms of tolerance also protect against autoreactive thymocytes
◦ Some self-antigens are “hidden” because only pAPCs express the correct costimulatory molecules needed to initiate immune responses
◦ Autoreactive naïve T cells can see the MHC/self-peptide complex on other cells, but won’t receive correct costimulatory signals
What is “anergy”?
high-affinity interactions without costimulatory ligands
