Lecture 11-12 - TCR and T cell development Flashcards
Major differences between TCR and Immunoglobulins
TCR only act as receptors
(Ig’s are receptors AND effector molecules)
Structure of the TCR complex
- TCR molecule (alpha and beta)
- CD3 molecules (epsilon/delta AND epsilon/gamma)
- ς-unit (intracellular)
CD3 chain function
transmits signals when TCR is activated
Two classes of TCR
alpha beta
gamma delta
Four regions of TCR
- Variable
- Constant
- Transmembrane
- Cytoplasmic tail
Immature T cells migrate from ___ to ___
Mature cells travel to the ___
Bone marrow to thymus
to the circulation as a ‘naive’ Tcell
What happens to T cells after they leave the thymus as mature cells?
They go to lymphoid tissue, where if they recognize antigens presented on DC, will mature into memory or effector T cells
Immature (Dp/Dn) thymocytes are found in the ____
Mature thymocytes (single positive) are found in ______
Immature = cortex
Mature = Medullary area
Most thymectomized patients still have T cell immunity due to
the amound of memory T cells in the periphery
Stem cell surface marker
CD34
Progenitor cell adhesion molecule
CD44
Surface molecules of a double negative thymocyte
CD2, CD5 (adhesion and signaling)
IL-7 receptor
CD1A
The alpha and beta chains differ in that..
alpha chain does not have a D segment
(Beta chain germline config is more complex)
TCR segment of the beta chain that rearranges first?
Which is second?
DJ first –> VDJ second
Even though the alpha TCR chain has no D segment, it does have _____ that contributes to diversity
Many more J segments
Total diversity of TCR’s is [less/greater] than immunoglobulins
TCR greater diversity
Which TCR chain is made first?
Beta chain
Steps to TCR rearrangement (7)
- Germline baseline configuration
- D-J rearrangement
- V- DJ rearrangement
- Surface expression of beta chain (cell proliferates!)
- alpha transcription starts
- Alpha VJ rearrangement
- Expression of alpha
- SELECTION can begin!
How many attemps at Beta chain rearrangement are possible?
2
After that the cell apoptosis-es
Successful rearrangemtne of one Beta copy…
blocks the other chromosome
Junctional diversity of TCR is mediated by __ and ___
How?
TdT and RAG enzyme
RAG = Cleaves hairpin and adds P nucleotides
TdT = adds N nucleotides
How many chances are there fore successful alpha chain rearrangement?
Multiple
Successful rearrangement of one of the alpha chains…
does not block that at the other
Therefore many T cells express two different alpha chains
When does a TCR decide it wants to be a gamma delta
anytime before rearrangement of the Beta chain
Successful rearrangement of gamma and delta chains before Beta means…
it will be a gamma delta T cell
Successful rearrangement of a B chain before a gamma delta chain means…
it still hasnt committed yet.
The cell HALTS its rearrangements and enters a stage of proliferation
What happens after the T cell has rearranged its Beta chain, and entered proliferative phase?
Three man race to the finish!!
It starts to rearrange the alpha, gamma, and delta chains to see if it will be an alpha/beta or gamma/delta cell.
First one rearranged successfully determines outcome
The two opportunities for a cell to become a delta gamma cell:
Gamma/delta’s race with BETA
Gamma delta’s race with ALPHA
The successful rearrangement of gamma delta signals…
for the cell to stop all rearrangement
Rearrangement of Alpha always…
eliminates the delta chain locus
(because it is always in between Va and Ja segments that join, and looping out the delta)
Most gamma delta T cells do not express..
CD4 or CD8
Function of gamma delta cells?
anti-bacterial / viral / tumor
Compared to alpha/beta, the gamma chain locus has ___ diversity
Less
List some antigens that gamma delta cells recognize
- HMB-PP (tuberculosis and malaria)
- Host MHC1b
- Nonprotein alkylamines
- HSP (TB and host)
- Superantigens
Unique feature of gamma delta function
Don’t need antigen processing and presentation via MHC
Structures of CD4 and CD8
CD4 is a linear monomer (D1-4)
CD8 is a dimer (looks like an 8!)
Checkpoint for Pre-TCR is _______
Checkpoint for TCR is _______
beta chain rearrangement
alpha rearrangement
To survive in thymus, Tcells need to…
bind self MHC, but not too strongly
Positive selection of T cells is carried out by ________ cells.
What do they express?
thymic epithelial
They express self MHC1/2 that are loaded with self pepties
Negative selection is carried out by ______ cells
Where are they?
Dendritic cells and MQ
In the cortico-medullary junction
The proportion of T cells that are positely/negatively selected is determined by…
Mathmatically, what are the effects of changing this?
the number of MHC molecules (N)
As (N) increases, positive selection increases arithmetically (N), while negative selection increases geometrically (N2)
What is the magic number (N) of MHC that will give the maximum T cell repertoire?
N= 13
If you have more isotypes than this, there will be too much negative selection
Major issue of mismatched bone marrow transplantation?
Positively-selected T cells (recipient) can’t recognize antigens presented by the MHC from donor’s antigen-presenting cells
DiGeorge syndrome patients lack
functional thymus
*symptoms similar to SCID (no thymic epithial cells for lymphocyte maturation)
Expansion of Tcell clones is an _____ process, occuring in secondary lymph tissues
antigen-dependent
Four major steps of T cell development (Summary)
- Double negative CD3- cells in subcapsular zone (proliferation)
- Double positive CD3+ in cortex – (positive selection)
- DP cells negatively selected at CMJ
- Mature cells (self restrictive, SP) leave in blood venules
