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.
One of the important parts in the study of Immunology.I prepared it for the sake of a seminar series competition conducted in my university. Now I thought of sharing it with others.
Altering the specificity of T cell receptor (TCR) is one of the popular strategies to genetically modify T cells to enhance the tumor-killing activity of T cells. From a tumor-reactive T cell or active anti-tumor T-cell antigens, the appropriate target sequence is introduced to modify T cells to target a broad range of tumors with improved specificity. https://www.creative-biolabs.com/car-t/cellrapeutics-tcr-technology.htm
This PPT is about immune system and immune therapy, some basic knowledge about Chimeric Antigen Receptor or CAR technology and its application on tumor therapy.
Introduction
Definition
History
Two hit hypothesis
Functions
Mutation in tumor suppressor genes
What is mutation
Inherited mutation of TSGs
Acquired mutation of TSGs
What is Oncogenes?
TSGs and Oncogenes : Brakes and accelerators
Stop and go signal
Examples of TSGs:
RB-The retinoblastoma gene
P53 protein
TSGs &cell suicide
Conclusion
References
One of the important parts in the study of Immunology.I prepared it for the sake of a seminar series competition conducted in my university. Now I thought of sharing it with others.
Altering the specificity of T cell receptor (TCR) is one of the popular strategies to genetically modify T cells to enhance the tumor-killing activity of T cells. From a tumor-reactive T cell or active anti-tumor T-cell antigens, the appropriate target sequence is introduced to modify T cells to target a broad range of tumors with improved specificity. https://www.creative-biolabs.com/car-t/cellrapeutics-tcr-technology.htm
This PPT is about immune system and immune therapy, some basic knowledge about Chimeric Antigen Receptor or CAR technology and its application on tumor therapy.
Introduction
Definition
History
Two hit hypothesis
Functions
Mutation in tumor suppressor genes
What is mutation
Inherited mutation of TSGs
Acquired mutation of TSGs
What is Oncogenes?
TSGs and Oncogenes : Brakes and accelerators
Stop and go signal
Examples of TSGs:
RB-The retinoblastoma gene
P53 protein
TSGs &cell suicide
Conclusion
References
immunological tolerance can be divided into two parts. they are central tolerance and peripheral tolerance. this slide contains information on development of central tolerance which include both B cell and T cell central tolerance.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Model Attribute Check Company Auto PropertyCeline George
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Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
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June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
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The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
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• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
2. 7/16/2022 2
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
3. 7/16/2022 3
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.
4. 7/16/2022 4
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.
5. 7/16/2022 5
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
7. 7/16/2022 7
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
8. 7/16/2022 8
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.
11. 7/16/2022 11
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…
12. 7/16/2022 12
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.
14. 7/16/2022 14
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.
15. 7/16/2022 15
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
16. 7/16/2022 16
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.
17. 7/16/2022 17
The TCR Complex
The T-cell receptor complex with TCR-α and TCR-β chains, CD3 and ζ-
chain accessory molecules.
18. 7/16/2022 18
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
20. 7/16/2022 20
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.
21. 7/16/2022 21
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.
22. 7/16/2022 22
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.
23. 7/16/2022 23
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.
24. 7/16/2022 24
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.
25. 7/16/2022 25
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.
26. 7/16/2022 26
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.
28. 7/16/2022 28
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.
.
29. 7/16/2022 29
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).
30. 7/16/2022 30
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.
31. 7/16/2022 31
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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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.
34. 7/16/2022 34
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.
37. 7/16/2022 37
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
39. 7/16/2022 39
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