The T cell receptor (TCR) is a heterodimer found on T lymphocytes that recognizes antigens bound to MHC molecules. It consists of either an alpha and beta chain or a gamma and delta chain. The TCR is associated with the CD3 complex consisting of five proteins that are necessary for cell surface expression and signal transduction. TCRs are generated through V(D)J recombination of gene segments and provide diversity to recognize a wide range of antigens. T cell activation requires recognition of antigen-MHC by the TCR along with co-stimulatory signals through molecules like CD28.

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T-cell Receptor
Presented By:
Dr.Debasish Sahoo
M.D(Microbiology).1ST Year
S.C.B.Medical College
Cuttack

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POINT OF DISCUSSION
o Definition & Characteristics of TCR
o Generation of TCR
o The TCR Complex
o TCR Co-Receptors
o T Cell Activation
o Associated Molecules of TCR complex
o Immunoglobulin superfamily

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DEFINITION
 The T cell receptor or TCR is a complex of
eight transmembrane proteins which consist
of two disulfide linked chains.
 It is found on the surface of T Lymphocytes
responsible for recognizing antigens bound
to MHC molecules.
 It is a heterodimer consisting of a and b
chains in 95% of T cells, whereas 5% of T
cells have g and d chains.

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TCR
 Mature T cells express one of two types
of TCR: a heterodimer composed either
of a and b chains or of g and d chains.
 T cells expressing ab receptors
account for 90% of T-cell helper function
and cytotoxic activity.
 The gd T cells, whose physiologic role is
still unclear.

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a b TCR
 a b TCR mostly found in thymus & peripheral
lymphoid organs.
 Is disulphide linked heterodimer of
.alpha subunit-40-50 kDa
.beta subunit-35-47kDa
 Each polypeptide chain contains two
extacellular Ig- like domain of 110 aa.
 The extracellular portion of the ab
heterodimer is structurally similar to the
antigen-binding fragment (Fab) of an Ig

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Structure of the TCR (αβ)
 Heterodimer
 α and β
chains
 approx
equal length

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Structure of the TCR (αβ)
 Short cytoplasmic tail-
cannot transduce
activation signal
 Transmembrane with
hydrophobic AAs
 Both α and β have a
variable (V) and
constant (C) region
 V region is
hypervariable,
determines Ag
specificity

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Structural characteristics of the TCR
The structure of TCR is very similar to
immunoglobulin Fab fragments
The V- domain of both TCR α-chain
and β-chain have 3 hypervariable or
complementarity determining regions
The V-region of the β-chain has an
additional area of hypervariability
(HV4) that does not normally contact
antigen and not considered a CDR.

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Structural characteristics of the TCR
 CDR3 is the main CDR responsible for recognizing
processed antigen,
 CDR1 of the alpha chain interact with the N-terminal
part of the antigenic peptide,
 CDR1 of the β-chain interacts with the C-terminal part of
the peptide.
 CDR2 is thought to recognize the MHC.
 CDR4 of the β-chain do not participate in antigen
recognition, but interact with superantigens.
 The C- domain of the TCR consists of short connecting
sequences in which a cysteine residue forms disulfide
bonds, which forms a link between the two chains.

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TCR

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Similarity with B-cell (Ig)
Each a and b chain consists of
 ‘Ig-like’ N-terminal variable region (V)
 Ig-like constant (C) domain
 Hydrophobic transmembrane region
 Short cytoplasmic region.
V-region of alpha & delta of
TCR is like v-region of L-chain with V&J
seg. similarly…

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Difference from B-cell
 TCR remain membrane-bound
 Contain only single antigen binding site
 No evidence of somatic mutation
 Junctional diversity greater in TCR
than antibody

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Generation of the TCR
TCR formation are similar to those of
B cell receptors.
TCR alpha chain is generated by VJ
recombination, whereas the beta chain
is generated by V(D)J recombination .
 Generation of the TCR gamma chain
involves VJ recombination, whereas
generation of the TCR delta chain occurs
by V(D)J recombination.

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T-cell Receptor complex
The biochemical signals that are triggered
in T cells by antigen recognition are
transduced not by the T cell receptor itself
but by invariant proteins called CD3 an z
(zeta), which are noncovalenlty linked to
the antigen receptor to form the TCR
complex.

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TCR and CD3 complex
 TCR is closely
associated with CD3
complex
 Group of 5 proteins
 Commonly called
“invariant” chains of TCR
 Role of CD3 complex
 CD3 necessary for cell
surface expression of
TCR
 transduces signal after Ag
interaction with TCR

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CD3
 TCRs occur as either of
two distinct heterodimers,
ab or gd, both of which are
expressed with the non-
polymorphic CD3
polypeptides g, d, e, and z.
 The CD3 polypeptides,
especially z and its
variants, are critical for
intracellular signaling.

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The TCR Complex
The T-cell receptor complex with TCR-α and TCR-β chains, CD3 and ζ-
chain accessory molecules.

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TCR α & β GENES & THE GENERATION
OF TCR DIVERSITY
 Diversity of TCRs required to recognize a
wide spectrum of antigenic determinants.
 TCR a and b genes use a strategy of
recombination similar to that of the
immunoglobulin genes.
 The germline TCR b-gene locus contains
20-30 V (variable), 2 D (diversity), and 13
J (joining) gene segments

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Genetic basis for receptor generation
 Accomplished by recombination of V, D and J
gene segments
 TCR β chain genes have V, D, and J
 TCR α chain genes have V and J

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Rearrangement of the TCR α and β genes.
During T-cell ontogeny, the TCR genes
rearrange , so that one of the Va segments
pairs with the Ja segment and a Vb segment
pairs with a Db and Jb segment.

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TCR with antigen and MHC
Activation of T lymphocyte
through a series of
biochemical events .
mediated by
 associated enzymes,
 co-rceceptors,
 accessory molecules
 transcription factors.

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Interaction of TCR with
Superantigens
 The super antigens act as clamp between
TCR and class II MHC providing signal to
the T cell.
 On T cell super antigens binds to V-beta
segments only without affecting D-beta
and J-beta regions.

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gd TCR
 The gd TCR are a second type of TCR.
 Their function remains largely unresolved.
 They do not recognize MHC-associated
peptides and are not MHC restricted.
 In mice and chickens they are found in the small
bowel mucosa and termed intraepithelial
lymphocytes.
 In humans they are found in the tongue, uterus
and vagina.

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Accessory molecules
T cells also express
other membrane
receptors that do not
recognize antigen but
participate in
responses to
antigens: these are
collectively called
accessory molecules.

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CD45
 CD45 is a large (180-220 kd)
transmembrane cell surface molecule that
is expressed by all leukocytes, including
all T lymphocytes.
 The cytoplasmic domain of CD45 has
tyrosine phosphatase activity.
 CD45 is required for the functional
coupling of the TCR and its PTKs.
 Naive T cells express CD45RA, whereas
memory T cells express CD45RO.

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COSTIMULATION BY CD28
 CD28, expressed as a homodimer on the
surfaces of all CD4 T cells and 50% of CD8
T cells.
 CD28 binds two distinct cell surface
molecules, B7.1 and B7.2, found on
dendritic cells, macrophages, and activated
B cells.
 The combination of TCR stimulation and
interaction of CD28 with its B7 ligands fully
activates T cells and results in greater
lymphokine production.

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COSTIMULATION BY CD28

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CTLA-4
 CTLA-4 shares considerable sequence
homology with CD28 and, like CD28, binds
B7.1 and B7.2 on the APC.
 Unlike CD28, however, CTLA-4 delivers
inhibitory signals to T cells, so that
engagement of CTLA-4 tends to strongly
diminish T-cell responses.
.

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CD2
 CD2 is a glycoprotien present on more
than 90% of mature T-cells and 50-70% of
thymocytes.
 This molecule contains two extracellular Ig
domains.
 The principle ligand for CD2 is LFA-3
(CD58).

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CD2
 CD2 functions both as an adhesion
molecule and signal transducer.
 The association of CD2 with the TCR
complex helps to aggregate the TCR in the
regions of cell–cell contact, allowing the
stabilization of low-affinity TCR/MHC
interactions.
 Finally, CD2 is involved in the regulation of
cytokine production by T cells.

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Integrins
 The major functions of T-cell integrins are
to mediate adhesion to APCs, endothelial
cells, and extracellular matrix proteins.
 The avidity of integrins for their ligands is
increased rapidly on exposure of the T-
cells to cytokines called chemokines and
after stimulation of T-cells through the
TCR.

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Integrins
Figure 6-11

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CD44
 CD44 is expressed by activated and
memory cells in comparison to naïve cells.
 This molecule is responsible for retension
of T cells in extravascular tissues at sites
of infection and for the binding to
endothelial cells at sites of infection and in
mucosal tissues.

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CD95 (Fas receptor)
 Activated T cells also express a
ligand for death receptor Fas (CD95).
 Engagement of Fas by Fas ligand on
T-cells results in apoptosis and is
important for eliminating T-cells.

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T-cell Subtypes
 T helper Th1 cells secrete pro-inflammatory
cytokines (IFN-g, TNF, and IL-2.
 Whereas T helper Th2 cells produce
cytokines that generally stimulate Ig
responses (IL-4, -5, -6, -9, and -10).
 These biases tend to be self-reinforcing: IL-
10 represses Th1 cell activity and IFN-g
inhibits Th2 cells.

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T cells

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Key steps in T cell activation
 APC must process and present peptides
to Ts
 Ts must receive co-stimulatory signal
 Accessory adhesion molecules stabilize
binding of TCR and MHC
 Signal from cell surface is transmitted to
nucleus
 Cytokines produced help drive cell
proliferation

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Three Steps to Activation

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Immunoglobulin superfamily
 The immunoglobulin
superfamily (IgSF) is a large
group of cell surface and soluble
proteins that are involved in the
recognition, binding, or
adhesion processes of cells.
 They all possess a domain
known as an immunoglobulin
domain or fold.
 Members of the IgSF include
 Adhesion molecules
(I CAM-1,V CAM-1)
 MHC
 TCR
 Cellular Receptor for Antibodies

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