Transcript The Generation of Diversity (GOD): How to Ensure

The Generation of
Diversity (GOD):
How to Ensure
Nonreactivity with
Self
The
Immunological
Orchestra
Richard Gershon,
Maestro
Goal: Develop TCR That Recognizes
and Binds Foreign Antigens
The receptor for antigens on the T cell surface comprises eight proteins.
(a) Two disulfide-bonded chains of the T cell receptor which form a heterodimer. These recognize
peptides associated with MHC molecules.
(b) Four chains, collectively termed CD3, that associate with the T cell receptor dimer and participate
in its transport to the surface of the cell. The CD3 complex together with the zeta chains, which form
a homodimer, transduce the signal after antigen has bound.
SOURCE: http://pathmicro.med.sc.edu/
Generating Functional T cells
• Prethymic T cells enter the thymus rudiment and
proliferate as large lymphoblasts in the subcapsular region of the thymus; result is a pool of
cells ready to differentiate.
• Here the cells become CD8 and CD4 positive
but expression is low.
• TCR genes are also rearranged in these cells
and the products may also be expressed on the
cell surface at low levels.
The T cell receptor heterodimer comprises two transmembrane glycoproteins, the alpha and beta
chains. There are two domains in the external part of each chain and these resemble immunoglobulin
variable and constant regions. There are sugar chains on each domain. There is a short sequence
similar to the immunoglobulin hinge region that connects the immunoglobulin-like domains to the
transmembrane sequence. This contains cysteines that form a disulfide bridge. The hydrophobic
transmembrane helical structures are unusual in that they contain positively charged amino acids
(basic amino acids). The alpha chain has two positively charged residues while the beta chain has
one.
SOURCE: http://pathmicro.med.sc.edu/
Generating Functional T cells
• As the cells mature, they
move into the cortex where
they adhere to cortical
epithelial cells which are long
and branched, providing a
large surface area to interact
with other cells. TCR
required.
• TCRs on the surfaces of
thymocytes interact with the
MHC molecules on the
epithelial cells—these
thymocytes have been
positively selected to survive.
• The cells that are not
selected are subject to
apoptosis and are
phagocytosed by
macrophages.
Generating Functional T cells
• As the thymocytes
migrate further into the
cortex of the thymus, the
expression of CD3, CD4,
CD8 and TCR increases.
• TCRs with self-reactivity
are deleted because of
contact with autoantigens
presented by dendritic
cells and macrophages.
This is negative selection.
• Cells that express CD4 or
CD8 appear and migrate
to the periphery by
specialized vessels in the
cortico-medullar region.
Goals of Thymic Education
1. Functional T cells in the periphery have to recognize
foreign antigens associated with self MHC, because
APC or target cells present foreign antigen associated
with self MHC (Class 2 for APC; Class 1 for targets).
2. Therefore, an individual does not need functional T cells
in the periphery that cannot recognize self MHC.
3. An individual also does not want functional T cells in the
periphery that can recognize self antigens associated
with self MHC because they could lead to damage of
healthy, normal tissues.
The Process of Thymic Education
1. T cells with the ability to bind to self MHC molecules
expressed by cortical thymic epithelial cells are retained.
This is known as positive selection. Those that do not bind,
die. Thus, T cells having a TCR that recognizes self MHC
survive.
2. T cells with the ability to bind with high affinity to self MHC
molecules associated with self molecules expressed by
dendritic cells and macrophages are killed. This is known as
negative selection. Those that do not bind are retained. As a
result of these two steps, T cells having a TCR that
recognizes self MHC and foreign antigen survive.
3. Each T cell that survives positive and negative selection in
the thymus and is released into the periphery retains its
specific T cell receptor (TCR).
Do we need to run through this again?
Animation has several positive features:
• attracting and directing attention;
• fostering mental model construction;
• representing information that involves
movement; and
• explaining complex phenomena.
M.S. Chan and J.B. Black. Proceedings of EdMedia2005, AACE.
http://www.bio.davidson.edu/Courses/Immunology/Flash/Main.html
But the system isn’t perfect….
Autoimmunity
• Breakdown of mechanisms responsible for
self tolerance and induction of an immune
response against components of the self.
• Activation of the immune system often
leads to tissue damage; disease results.
• Disease may be organ specific or
generalized.
• Evidence for genetic predisposition.
Possible mechanisms
• Sequestered or late-developing antigen;
not present during “education”
• Escape of auto-reactive clones
• Cross-reactive antigens, including
exogenous antigens (pathogens) and
altered self antigens (chemical and viral
infections)
• Loss of suppressor cells
The Search for the TS
• T cells that suppress the immune response were
discovered in the early 1970s. Richard Gershon of Yale
University coined the term "suppressor T cell" after
experiments suggested that a certain type of T cell
suppressed immune responses through a soluble factor
and not through direct interaction.
• Many prominent groups tried—without success- to
characterize these suppressing factors. Plus, the genes
for the postulated suppressing factors couldn't be found.
Many doubted that they were real.
• A different line of study lead to an understanding of
negative regulation by T cells.
The Search for the TS
• In 1995, Shimon Sakaguchi showed that removing a subset
of CD4+ T cells that express a marker called CD25 resulted
in severe autoimmune disease in mice (J. Immunol. 155,
1151, 1995). The condition resembled the one described in
the 1969 study. Sakaguchi called the cells regulatory T cells.
• It is clear that these regulatory T cells—or Tregs—are crucial
to keeping the immune system in check, although the exact
mechanism as to how they suppress their target cells has
not yet been resolved.
• Tregs are important in suppressing autoimmune disease in
that they suppress T cells directed against self antigens.
Tregs in Humans
• Tregs shown to suppress immune responses, including
the activation of CD4+ and CD8+ T cells and also
dendritic cells. They are important because, for example,
not all T cells against self-antigens are deleted in the
thymus, and Tregs are thought to suppress the activity of
those that escape. They can also suppress T-cell
activation in response to pathogens.
• In 2001, several groups identified a similar population of
Tregs in cultured human cells. Defined as being high
expressers of CD25
• Several soon identified one more marker: the
transcription factor Foxp3.
Generation of Tregs
International AIDS Vaccine Initiative Report Vol. 11 (4), July - Aug. 2007.
Not-so-innocent bystander: Regulatory T cells suppress the immune reactions of neighboring T cells.
This “bystander suppression” happens when a Treg that recognizes a single peptide from one particular
antigen also suppresses the responses of T cells that recognize different peptides from that or any other
antigen presented by the same antigen-presenting cell. Tregs specific for a given antigen can thereby
imbue a tolerance to several antigens. It is not yet known whether the Tregs directly restrain the effector
T cells or alter the antigen-presenting cell’s ability to activate them. SOURCE: Harvard Focus March 21, 2008
Do we need to run through this again?
ab-direct.com - Regulatory T cell animation