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T Cell Maturation and Activation

T cells are generated in the bone marrow and


educated in the thymus.

The generation of a mature T cell in the mouse

Pre-T cell

V-J

In the thymus

< 5% of thymocytes develop into double-negative CD3+ T cells

Figure 7-13 part 2 of 2

Time course of appearance of and


thymocytes during mouse fetal development

After the double negative (DN) thymocytes


express a productive rearranged TCR chain,
the newly synthesized b chains will associate
with a 33-kDa glycoprotein called pre-T
chain together with CD3 to form the pre-T
cell receptor (pre-TCR).
Although the ligand to pre-TCR is unknown,
pre-TCR will deliver several important signals.

Structure and activity of pre-T cell receptor (pre-TCR)

Before the double negative pre-T cells


advance to next stage, they begin proliferate
before the TCR- chain rearrangement take
places.

The proliferation phase prior to the


rearrangement of -chain increases the
diversity of the T cell repertoire by generating
a clone of cells expressing a single TCR
chain with a different chain.

T Cell Maturation undergo 2


Selection Processes in the Thymus:
Positive selection: permits the survival of only those
T cells whose TCRs are capable of recognizing
self-MHC molecule.
MHC restriction
Negative selection: eliminates T cells that react too
strongly with self-MHC plus self-peptide.
Self tolerance
~98% of thymocytes die by apoptosis, it is expensive for the
host. However, both processes are necessary to
achieve MHC restriction and self-tolerance.

Thymus is Important in Selection of T Cell Repertoire

Thymus
express
MHC H2b
(Containing LCMV specific cytotoxic T cells)

Zinkernagel et al.
T cells only recognize targets expressing H-2b:
the MHC haplotype of the thymus determines their MHC restriction.

What are cells important for positive and


negative selections in the thymus?
Thymic stromal cells include:
Epithelial cells
Dendritic cells
Macrophages
They all express class I MHC molecules and high
levels of class II MHC molecules to help the
selection processes.

Selections occur in the cortical region of the thymus

Only those cells


whose TCR
recognizes a selfMHC molecule are
selected for
survival

Only those cells


whose TCR has
an intermediate
affinity for selfMHC molecule are
selected for
survival

What are essential elements for


positive and negative selections?

Class I MHC molecules are required for positive selection of CD8 T


cells and class II MHC molecules are required for CD4 T cells

The TCR-MHC Interaction is Required for Positive Selection

Most
thymocytes
express the
TCR transgene

CD8 thymocytes fail to


mature because lack of
interaction with MHC
molecules

Evidence for Negative Selection: self antigen and MHC are required
(CD8)

Most thymocytes
express the TCR
transgene

Thymocytes
reactive to
self-antigen
are deleted
during thymic
selection

Hypotheses to explain the MHC-dependent


positive and negative selection
Avidity hypothesis: the outcome of MHC-peptide binding
by TCR depends on the strength of the signal delivered by the
receptor on binding, and this will, in turn, depend on both the
affinity of the TCR for MHC-peptide complex and the density
of the complex on thymic epithelial cells.

Differential-signaling hypothesis: the signals leading


to positive and negative selection are different. The quality
rather than quantity determines different outcome.
Both hypotheses have supporting evidence, it is possible
that no single mechanism accounts for all the outcomes in
the thymus.

Fetal thymic lobes are excised and place in culture. At this stage,
thymus contains mainly CD4-CD8- thymocytes. It is a good model
to study the details of thymic selections

Evidence Supports the Avidity Hypothesis

No peptide on
MHC class I
molecules

The avidity of the


TCR-MHC
interaction was
varied by the use
of different
concentrations of
peptide.

leads to positive
selection
leads to negative
selection

How a double positive precursor become


CD4+ or CD8+ cells?
Instructive model: the interaction between TCR,
CD8, CD4, and MHC class I or class II instruct a
cell to differentiate into either CD8+ or CD4+ cells.
Stochastic model: CD4 or CD8 expression is
switched off randomly.
So far, it is not possible to choose one model over
the other.

Summary:
The surface expression of pre-TCR is important for
pre-T cell development. Pre-TCR will deliver
signals to stop further TCR chain rearrangement,
begin proliferation and CD4/CD8 expression, and
possibly start TCR chain rearrangement.
T cell maturation occurs in the thymus where MHC
restriction and self tolerance are achieved. (by
positive and negative selections)
MHC molecules and the interaction between
thymocytes and thymic stromal cells are important
for the development of mature T cells.

T Cell Activation
T cells are activated in the secondary lymphoid tissues

Distribution of antigen-presenting cells in


the lymph node
Strongest
activators of
nave T cells

Nave T cells encounter antigen during recirculation

The initiation of TCR signaling


APC

Ca2+
PKC

SLP-76

ZAP-70 phosphosylates
adaptor proteins that recruit
components of several signal
pathways

Immediate early gene expression after T helper cell activation

Early gene expression after T helper cell activation

Late gene expression after T helper cell activation

Two signals are necessary for full T cell activation:


Signal 1: generated by interaction of MHCpeptide with the TCR-CD3 complex

Signal 2: generated by interaction of CD28 on


the T cells and members of the B7 family on the
APC, it is also called co-stimulatory signal

Lack of co-stimulatory signal results in clonal anergy

Anergy: cells are alive but not functional

Lack of co-stimulatory signal results in clonal anergy

Lack of co-stimulatory signal results in clonal anergy

Co-stimulatory signals are required for full T cell activation


Expressed on resting and
activated T cells

Expressed on
activated T cells

Expressed on dendritic cells


activated macrophages and
activated B cells

CTLA-4, an inhibitory receptor for B7


molecules, is up-regulated after T cell activation

Comparison of different antigen-presenting cells

Comparison of different antigen-presenting cells

Figure 8-18 part 2 of 2

Superantigens induce T-cell activation by binding the TCR and


MHC II simultaneously

Superantigens: proteins that bind simultaneously to TCR V chain and chain of


MHC class II. Superantigens induce T cell activation and proliferation.

Exogenous superantigens are mainly exotoxins secreted by grampositive bacteria

Endogenous Superantigens: cell-membrane proteins


encoded by certain viruses that infect mammalian cells.

The activation by superantigens is polyclonal.


The massive activation by superantigens results in
overproduction of T helper cell cytokines, leading
to systemic toxicity.

Activation of T cells generate effector and memory T cells

Nave T cells: cells never meet antigens before. They


can only be activated by dendritic cells.

Effector cells: short-lived cells with special functions


such as cytokine secretion and B-cell help and cytotoxic
killing activity. Effector cells are derived from nave or
memory cells after antigen activation. TH1 and TH2 subsets.

Memory cells: long-lived resting cells that are derived


from nave and effector cells. They respond faster and
stronger to a subsequent challenge with the same antigen.

CD4+CD25+ regulatory T cells: cells that can inhibit


the proliferation of other T cell population in vitro and also
inhibit the development of experimental autoimmune
systems.

Termination of T cell activation

Two pathways
Lead to apoptosis
In T cells

Activation-induced
cell death (AICD)

Failure of apoptosis causes defective lymphocyte homeostasis


Canale-Smith symdrome:
lpr/lpr mice:Fas mutant
gld/gld mice: FasL mutant

fas+/- , elevated lymphocyte numbers,


Hyper-gammaglobulinemia,
Autoantibodies against RBC and
platelets

Blood samples

Summary:
Two signals are required for full T cell activation, one
from TCR-CD3 interactions with MHC-peptide
complex, the other from CD28 interactions with B7
family proteins. Thus, CD28 and B7 family are called
co-stimulatory molecules.
Lack of co-stimulatory signals in T cells results in
clonal anergy or sometimes apoptosis.
What are superantigens?
Fas-mediated and activation-induced cell death are
used to remove activated T cells and maintain T cells
homeostasis.