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Discuss the role of MHC-peptide TCR interaction affinity in shaping T-cell fate
There are many different T cell fates, the first of which is decided early on in an immature T cells life,
in the thymus
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At this point T cells that will be beneficial to the host during
infection will be selected and the non-beneficial or potentially harmful T cells will die
...

This causes activation of T cells where they proliferate and differentiate into different types of T cells
which have a variety of effector functions to help combat any infection within the host
...
It is
important to understand the structure of both the TCR and MHC molecules in order to appreciate
how binding between them occurs, as both immature and mature T cells depend on this interaction
affinity to lead them through a series of checkpoints that determines the outcome of their fate
...

MHC molecules are highly polymorphic with the majority of differences occurring in the peptide
binding groove
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There are two classes of MHC, class I and class II, which
are bound by different T cell groups helping to shape their fate
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It would be most useful for the MHC to have a general, nonspecific binding to present all possible harmful peptides to T cells, however due to steric
conformations of peptides the peptide binding groove is forced to be semi specific
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The binding of peptide to MHC stabilizes the MHC molecule as it forms an integral part of
the structure
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This means that the TCR has to recognise not only the foreign antigen but also, to a
certain degree, self-MHC molecules
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Compared to the MHC molecule, the TCR is exquisitely specific for the antigen it binds
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Both chains have a variable section with complementarity
determining regions (CDRs) and it is this variable domain which confers antigen specificity
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The
fate of T cells can only be decided once a signal has been sent into the T cell via TCR binding;
however due to short cytoplasmic tails of the TCR this molecule cannot transfer signals
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The binding of the TCR with
antigen and MHC causes a conformational change between the TCR and CD3 which transfers a signal
into the T cell
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T cells develop and mature from pluripotent hematopoietic stem cells which have migrated from the
bone marrow into the thymus
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The first stage in deciding T cell fate is thymic education where thymocytes are positively
or negatively selected if they have the correct TCR properties that will be useful to the host in
infection
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These double
positive thymocytes only have a short life span and require the engagement of their fully formed
TCR in order to survive 3
...
Beneficial T cells must have TCRs that recognise this self-MHC due to the
processed peptide basically becoming part of the MHC molecule; hence the selected TCRs must be
able to recognise self-MHC in order to bind to the antigen it is specific to
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The fate of the remaining 10% of T cells that can
recognise self-MHC are functionally selected on a sliding scale that is directly related to the affinity
of interaction of the TCR for the self-MHC: self-peptide complex, as during these processes the selfpeptides bound to the MHC molecules, are also recognised
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The diagram shows there are currently four known fates which can be selected
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If the TCR has the ability to bind to the self-MHC: self-peptide complexes, there will be
two opposing outcomes which are based on the strength of the affinity of the engagement
...
This
selection occurs in the thymic cortex via cortical thymic epithelial cells (cTECs) which have very long
processes that branch out into the cortex which is packed with double positive thymocytes
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The processing of this peptide
requires specific enzyme subunits which are present and expressed by the cTECs 5
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When a lymphocyte undergoes gene rearrangement to form a TCR, the random generation allows
for a high possibility that the TCR will recognise self-antigens6
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This is called central tolerance and occurs in different
2

microenvironments, both in the cortex and medulla of the thymus via cTECs, medullary thymic
epithelial cells (mTECs) and dendritic cells (DCs)7
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AIRE binds to many gene
sequences and switches on their expression in the thymus so that tissue-specific peripheral antigens
are expressed on the mTECs
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This negative selection is very important in removing potentially selfreactive cells, as the thymocytes have not recognised self-antigen as ‘self’, but sees the antigens as
foreign therefore binding to them tightly8
...
g
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There is one more pool of thymocytes that develop in the thymus called regulatory T cells (Tregs)
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These Tregs show development at
a range of affinities for self-peptides; however optimal affinity is towards the higher spectrum
...
As shown in figure 1 the affinity for this development is in between the affinities for
positive and negative selection
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Here, they are susceptible to the high levels of co-stimulatory molecules present during
an infection, which can cause activation allowing them to be auto-reactive and be potentially
damaging the host
...
g
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Within the periphery there are many factors which contribute to the way T cells are stimulated
leading to proliferation and differentiation into specific T cell phenotypes
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If the
CD4/8 decides ‘yes’ and TCR: MHC-peptide binding occurs, then the CD4/8 increases the affinity at
the TCR: MHC junction and causes recruitment of signalling molecules activating the T cells to
combat infection11
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CD8+ T cells
recognise MHC class I becoming cytotoxic T cells
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Studies have shown that the TCR on Th1 cells and
Th2 cells have some structural differences in their CDRs
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In conclusion, it is very important for the host to produce a functional repertoire of T cells that
recognise MHC which is specific to each individual host, allowing T cells to provide protective
immunity during invasion and infection via the recognition and binding to foreign antigens
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These two processes are based on MHC-peptide TCR
interaction affinity, showing how crucial the strength of the interaction is in allowing T cells to
mature and in shaping T cell fate
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(Word count: 1,819)
References
1

Goldrath AW and Bevan MJ
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Nature
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2

Xing Y and Hogquist KA
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Cold Spring Harbor perspectives in biology
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3

Murphy K, Travers P, Walport M
...
7th edition
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4

Klein L, Kyewski B, Allen PM, Hogquist KA
...
Nature Reviews Immunology
...

5

Moran AE and Hogquist KA
...
Immunology
...


6

Nemazee D
...
Nature Reviews
Immunology
...

7

Anderson G and Jenkinson EJ
...
Nature
Reviews Immunology
...

8

Koehli S, Naeher D, Galati- Fournier V, Zehn D, Palmer E
...
Proc Natl Acad Sci USA
...

9

Wing JB and Sakaguchi S
...
European Journal of
Immunology
...

10

Taams LS, Palmer DB, Akbar AN, Robinson DS, Brown Z, Hawrylowicz CM
...
Immunology
...

11

Artyomov MN, Lis M, Devadas S, Davis MM, Chakraborty AK
...
2010;107(39): 16916-16921
...
Differential Antigen Sensitivity and costimulatory Requirements
in Human Th1 and Th2 Antigen-specific CD4+ cells with similar TCR avidity
...

2003;170(3): 1218-23
...
Positive and negative selection of the T cell repertoire:
what thymocytes see (and don’t see)
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2014;14: 377-391

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