淋巴细胞基因重排

T Cell Receptor (TCR)
T Cell Receptor (TcR)
•In many ways, the TcR resembles antibody or surface Ig.
•T cells responses are antigen specific.
•Similar to B cells, T cells possess an antigen specific and clonally restricted receptor.
•Genomic organization of TcR gene families and the mechanism of diversity generation of component chains of TcR are similar to B-cell receptor chains.
•Similar to Igαand Ig-βcomplex of B-cell receptor, TcR is associated with a signal–transducing complex, CD3.
T Cell Receptor (TCR)
On the other hand, TCR also differs from B cell receptor (Ig)in many ways.
•TCR is membrane bound and in contrast to B-cell receptor (BCR) (Ig), it does not occur in a soluble form.
•In contrast to BCR, most TCR are not specific to antigen alone rather they are specific to antigen combined with a MHC molecule .
Self–MHC restriction of the TcR •In 1974, Zinkelnagel and Doherty showed that
antigen recognition by T cell is not specific for the antigen alone rather it is specific for the antigen associated with MHC molecule.
•They showed that T cells recognize the antigen only when it is presented by self-MHC molecule.
•This phenomenon,
called ‘self-MHC
restriction’,
differentiates
recognition of antigen
by T cells and B cells.
•Dohorty and
Zinkelnagel were
awarded Nobel Prize
for this work in 1996.
Model for MHC restriction of TCR Two models were proposed
1.The dual receptor model:Two separate TCR;
one for antigen and one for MHC molecule.
2. The altered-self model:Single TCR recognizes
an alteration in self-MHC molecules induced
because of association with foreign antigen.
•Kappler and Marrack showed that specificity for both antigen and MHC molecule resides in
a single receptor.
•At present, ‘altered-self model’is an accepted model for MHC restriction of TCR.
TCR Structure
•Consists of an αand βchain, or a γand δchain.
•In human and mouse, majority of T cells express the αβheterodimer; the remaining T cells (small %) express the γδheterodimer
•No αδ, or γβT cells exist.
•Approximately 105TCR molecules are present on the surface of a T cell.
•Each chain has a variable (V) and a constant domain (C).
•The V domains in both αand βchains contain 3 hypervariable regions which are equivalent to complimentarity determining regions (CDRs) present in Ig light (L)and heavy (H)chains.
TcR Structure
•The βchain also contains fourth hypervariable region but it does not normally contact antigen and is not considered CDR.
•The TCRs are transmembrane, insoluble proteins.
•Transmembrane domains of both chains contain positively charged amino acid residues which play important role in interaction with CD3 complex.
•The most αβTcRs interact with peptide antigens presented by MHC molecules .
TCR Structure
•Certain αβT cells react with nonpeptide
antigens(carbohydrate and lipids) presented by CD1 molecules.
•In contrast to αβTCR, γδ
TCR exhibits limited diversity.
•The γδT cells react with antigen (e.g. phospholipid antigen of Mycobacterium tuberculosis) that is neither processed or presented in the context of a MHC molecule .
TCR is a member of Ig superfamily
•TcR molecule resembles
a Fa
b fragment and is
monovalent.
Diversity of the TCR
•Diversity is achieved by gene rearrangement,
similar to the Ig/Ab molecule.
Ig kappa light chain rearrangement
V and J
rearrangement
Ig heavy chain rearrangement
V, D and J
rearrangement
Diversity of the TCR
•The functional TCR is produced by rearrangement of
–V and J segments in α-chain and γ-chain
families and
–V, D, and J segments in the β-chain and δ-
chain families.
•Just as any heavy chain may combine with any light chain in antibodies, any TcR αchain may combine with any TCR βchain.
•While the same rules apply for the γδ-TCR, UNLIKE antibodies, there is no mixing between the αβand the γδchains.
•In a given T cell, the αβTCR receptor can not be coexpressed with the γδreceptor.
Mechanism of TCR DNA rearragement
•The αchain
like Ig L chain
is encoded by
V, J, and C
segments.
•The βchain
like Ig H chain,
is encoded by
V, D, J and C
gene
segments.Mechanism of TCR DNA rearragement •Unlike Igs, the TCR is expressed ONLY in
membrane bound form; thus no differential
RNA processing is required to produce
membrane and secreted forms.
•Unlike Ig H chain germline DNA which has
multiple C gene segments, TCR α-chain has one
C segment and β-chain has two C segments
only.
•Unlike B cells,
βand δTcR genes may rearrange as V-D-D-J or (less frequently) V-D-D-D-J.
Other similarities/differences to Ig •Unlike Ig,no somatic hypermutation occurs in
the TCR.
•Like B cells, a single T cell only expresses a single TCR and is regulated by allelic exclusion.
•Allelic exclusion is less stringent for TCR α-chain genes than for β-chain genes.
•Once the T cell leaves the thymus, no further alteration occurs within the TCR coding sequence-no class switching, no hypermutation.
•This ensures that T-cell specificity does not change after thymic selection and reduces the possibility of generating self-reactive T cells.
Schematic diagram of rearranged αβ-TCR genes
Ig
TcR Recombination signal sequences (RSS)
Only occurs in heavy chain and not in light chain.
occurs in all TCR chains.
T-cell receptor complex: TCR-CD3
•The TCR αβor γδproteins encode specificity .
•Like Ig αand Ig βchains in B cells, additional proteins (CD3 dimers ) are responsible for
signaling through TCR after antigen interaction.•CD3dimers do not effect the interaction with antigen.•CD3 is a complex of five invariant polypeptide chains (epsilon, delta, zeta, eta and gamma) that associate to form three dimers .•TCR closely associates with CD3, forming a TCR-CD3 complex.•CD3 expression is required for the expression of αβor γδTCR.
Immunoreceptor tyrosine-based activation motifs (ITAMs) interact with tyrosine kinases and play important role in signal transduction.
The TCR Accessory Molecules
•The TCR binds to antigen-MHC
complex, but additional accessory membrane molecules also play important role in antigen
recognition and T cell activation.•The most important of these are CD4 and CD8 molecules .•CD4 +ve T cells: largely helper T cells •CD8 +ve T cells: largely cytotoxic T cells •CD4 and CD8coreceptors bind to conserved regions of MHC class II and class I molecules respectively.
Additional molecules on the T cell surface also play a role in
stimulation.
3-D TCR-Peptide MHC
structures
•Read this section of the book, but you will NOT be tested on it.
Alloreactivity of T cells
•Graft rejection reactions occur as a result of direct response of T cells to MHC molecules.
•T cells respond to allografts and MHC molecules are considered alloantigens.
•Due to the presence of extreme polymorphism of MHC, most individuals of the same species are considered to be allogeneic.
•Generally, CD4+ T cells are alloreactive to class II alloantigens and CD8+ T cells respond to class I
alloantigens.
•Alloreactivity is puzzling for two reasons
–T cell response to alloantigens contradicts the notion
that T cells can respond only to foreign antigen plus
self-MHC molecules as in alloreativity,T cells recognize
a foreign MHC molecule directly.
–Frequency of alloreactive T cells is quite high (1-5% of all T cells). It contradicts the clonal selection theory.
Alloreactivity of T cells •Possible explanation:TCR specific for a foreign antigenic peptide plus self MHC can also cross-react with certain allogeneic MHC molecule.•As allogeneic cells express on the order of 105 class I MHC molecules per cell, T cells even expressing low affinity cross-reactive receptors might be able to bind.•Foreign antigen
is usually
sparsely
dispersed on
APCs or altered
self cell.
•This limits the
responsiveness
to only those T
cells bearing
high-affinity
receptors.
Next Lecture •Chapter 10-T Cell maturation, activation and differentiation.。