T cell Development

Figure 1: The TC Receptor

TCR vs. BCR
Similarities
o Ag binding by CDR3
o Ig domain proteins
o Associated with other signaling proteins
o Somatic recombination to generate diversity
Differences
o No secreted TCR
o TCR binds self-protein, MHC:Ag (CDR1/2:CDR3)
o No somatic hypermutation
o Different affinity maturation
o Little to no TCR rescue
o or

Recognition of MHC
TC recognize self MHC to undergo their effector function
TCs against LCMV Ag will only kill if it is presented on the right MHC
10% of TC are alloreactive

Figure 2: TCR:MHC Specificity

TCR
More limited diversity
Non-MHC or non-classical MHC restricted (CD1d)

NKT cells
NK cells with a TCR (usually )
Non-classical MHC
Limited diversity

TCR
2 receptor hypothesis
o Originally believed there was an Ag receptor and 1 other receptor that allowed TC
recognition
o It is now known that MHC both presents Ag and is recognized by TC
Extremely diverse
Recognize classical MHC I/II
Chromosomal separation of TCR subunits
o TCR, chr7
o TCR, chr21
o TCR or , chr 14


Figure 3: MHC
Figure 4: TCR contact with MHC
Figure 5: Location of CDRs on MHC

CD4/CD8 Co-receptors
Distinguish MHC I and II
o TCR are too low affinity to MHC to recognize
Binds non-polymorphic regions of the MHC (non-Ag presentation area)
CD4
o Recognizes MHCII
o Binds the or 2 chain
CD8
o Recognizes MHCI
o Homodimers or heterodimers or
o Binds 1/2 on the MHC

Figure 6: TCR Co-receptors

TCR Diversity
BCR do not rearrange in TC
o Commitment is made prior
o Limits TC to recognizing Ag presenting cells
Theoretical diversity
o 10
27
different TCR
Real diversity
o There is a lot more low-affinity TCR and much less high affinity TCR
o High affinity TCR probably recognize common pathogens

Figure 7: Real TCR Diversity

TC Development
IL-7 is absolutely necessary for TCs
NOTCH is the essential signal for determining TC over BC
FOXN1 controls thymic development (not HSC)
o < 3 months old, pT (DN) cells express CCR7 for thymus homing (thymus has HEV)
o > 3 months old, pT (DN) cells express CCR9 for thymic homing
CXCR4 for thymic cortex

Figure 8: From HSC to pT

Progress from DN1 to DP
o DN2 on express CD25, the chain of the IL-2R converting it to a high affinity receptor
TC proliferation
o Following DN3, decision is made to become cells or continue to DN4
o DN4 cells express TCR and pT
o DP cells express TCR and CD4/8
Signal from :pT or shuts off RAG1/2
o Tests for functional expression then re-expresses RAG for chain
o Inhibited by arrangement

Figure 9: TC Development to DP
Figure 10: the IL-2 Receptor
Figure 11: Rearrangement Inhibition

Clonal Selection Theory
Each TC expresses a single receptor
In reality, 50% of TC have more than one
Most often, only 1 TCR recognizes MHC:Ag
o The others never do

TCR Allelic Exclusion
Rearrangement of 1 allele excludes the other
Not 100% true
For BCR, you get receptor editing (new rearrangement)
For TCR, minimal editing
o Too many TCR genes, probably too complicated to try again

Figure 12: TCR Editing
Figure 13: Pre-TCR signaling

pT
Not just a surrogate LC
Modifies TCR signals
Binds CD3 complex
Different signaling than
o No accidental activation

For TC
1. Decrease RAG1/2
2. CCR9, CXCR4 (exit thymus)
3. CCR7 (towards medulla)
4. CD25 (proliferate)
5. S1P1R (exit thymus)

For TC
1. RAG1/2
2. CD25 (proliferate)
3. RAG1/2, pT
4. Rearrange TCR
a. Not + selection, only a test for surface expression
5. Positive selection occurs by cortical epithelial cells
a. Detection of self-MHC recog
b. If there is proper MHC detection, cells survive
c. Better interaction with MHCI leads to CD8, and MHCII to CD4
i. Not true, begins by downregulating both then introducing them one by one
ii. If there is a positive signal for CD4, then cells become CD4 SP or Tregs
iii. If there is signal interruption, cell switches to downregulating CD4 and becomes
CD8
iv. If the signal is still negative, the cell dies
d. Strong positive signal means survival
e. CEC are radioresistant, not BM derived
6. Negative selection is carried out by medullary epithelial cells that express self-antigen via AIRE
a. Strong positive signal means cell death (self-reactive)
b. MEC are radiosensitive, BM derived

Figure 13: TC Selection

CD4 vs. CD8
Not as simple as MHC I or II recognition
Closer to the instructional model
CD4/CD8 increase avidity for MHC

Figure 14: CD4 vs CD8

CD4 T
reg
vs. T
H
Does not undergo positive selection

Control of Self Protein Expression
MEC express AIRE (a transcription factor)
o Turns on all genes