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TODAY. T LYMPHOCYTE DEVELOPMENT . The TCR is a heterodimer composed of an a and a b chain. Each chain contains a variable (V) and constant (C) region. THE T CELL RECEPTOR (TCR).

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slide1

TODAY

T LYMPHOCYTE DEVELOPMENT

slide2

The TCR is a heterodimer composed of an a and a b chain.

Each chain contains a variable (V) and constant (C) region.

THE T CELL RECEPTOR (TCR)

The V and C regions are similar in structure to the V and C regions of Antibodies. Likewise, the V regions contribute most to antigen recognition.

In contrast to Antibodies, TCR are anchored in the plasma membrane and are not secreted.

slide3

Both are composed of two chains that combine to form variable and constant domain.

Both have flexible hinge regions.

In contrast to an antibody, the TCR is directly and permanently anchored in the plasma membrane. Thus, the C-terminus has no effector functions, it is needed for signaling.

The TCR compared with a free Ig molecule.

slide4

B CELL AND TCR-MEDIATED ANTIGEN RECOGNITION

1. TCR recognize peptides presented by MHC molecules. B cell receptor recognizes antigens without a requirement for presentation.

2. Recognition is mediated by variable domains.

3. TCR does not perform effector functions.

slide5

ANATOMY OF AN MHC-PEPTIDE-TCR COMPLEX

TCR

1. Antigenic peptide contacts the 1 and 2 domains of the MHC I molecule

V

2. Both the a and b chains of the TCR interact with the peptide.

Ag

Ag

V

Ag

1

1

2

2

3. Additional TCR residues interact with the MHC molecule.

2

2

3

3

MHC I

MHC I

slide6

APC present antigens to T cell on major histocompatibility complex (MHC) class I and class II molecules.

APC

APC

MHC II

MHC I

CD8

CD4

TCR

TCR

CD4

CD8

TCR

TCR

Th : CD4

Tc : CD8

T Ag are linear molecules in the context of MHC

slide7

THE TCR INTERACTS WITH THE PEPTIDE AND THE MHC

antigen

CD4 and CD8 interact with invariant residues on MHC class II and I.

antigen

antigen

CD4 and CD8 do NOT interact with the antigenic peptide.

Thus, the specificity of the response in not determined by the identity of the antigen. It is determined by the nature of the cell presenting the antigen.

slide8

CD4/CD8 Distinctions fine-tune the adaptive response.

Extracellular microbes: captured and presented on class II by APCs (macrophages, B cells). CD4 T cells help B cells produce antibodies and macrophages ingest and destroy. Thus, CD4 T cells activate best defenses against extracellular microbes.

slide9

CD4/CD8 Distinctions fine-tune the adaptive response.

Intracellular microbes: antigens from cytoplasmic microbes are captured and presented on class I by all nucleated cells. CD8 T cells directly eliminate infected cells. Thus, CD8 T cells activate best defenses against intracellular microbes.

slide10

The end result: a naïve CD4 or CD8 T cell

that recognizes a 3 dimensional surface comprised

of both peptide and MHC.

What a T cell recognizes in an ‘antigen’

is a unique combination of MHC

haplotype and peptide with the

recognition assisted by either CD4 or

CD8.

slide11

FEATURES OF TCR-MEDIATED

ANTIGEN RECOGNITION

1. TCR recognize peptides presented by MHC molecules.

2. Each clone is specific for a single antigen.

3. Antigen recognition is mediated by specific domains of the TCR.

4. Signaling triggers T lymphocyte activation.

slide12

During T cell development

alpha chain V, J and C

genes recombine to

form the T cell alpha gene

that characterizes

that T cell.

The beta chain gene is

formed from different

V, D, J, and C gene

recombination.

TCR proteins on different T cells arise from gene rearrangement

of multiple germ line genes (just like BCR gene rearrangement).

slide13

Recombinase rearranges V and J gene segments to form an alpha chain.

ALLELIC EXCLUSION

PATERNAL

MATERNAL

Va

Ja

Ca

Va

Ja

Ca

Each individual inherits maternal AND paternal alpha chain genes.

If the recombination reaction is productive, recombinase is shut off at the other alpha chain locus.

Prevents individual cells from expressing more than one TCR.

The same event occurs during BCR rearrangement.

slide14

1

2

T cell progenitors (thymocytes)

migrate from bone marrow to

the thymus.

TCR genes rearrange in the thymus to

produce T cells, which then migrate to

peripheral lymphoid organs to find antigen

TCR rearrangement occurs in the thymus.

slide15

T LYMPHOCYTE MATURATION IN THE THYMUS

THYMIC

EPITHELIAL

CELL

MHC-peptide

TCR

T cells that bind MHC-peptide complexes survive (positive selection).

TCR

Positive selection

6. Negative and positive selection sorts out useful T lymphocytes from useless, or potentially dangerous T lymphocytes.

Positive selection ensures that T cells CAPABLE of interacting with peptide-MHC complexes remain alive.

slide16

T LYMPHOCYTE MATURATION IN THE THYMUS

THYMIC

EPITHELIAL

CELL

MHC-peptide

TCR

CD4

T cells that bind Class II MHC-peptide complexes preserve expression of CD4 and lose CD8.

CD8

TCR

CD4

TCR

6. Negative and positive selection sorts out useful T lymphocytes from useless, or potentially dangerous T lymphocytes.

Thus, CD4 T cells develop on the basis of the ability of their TCR to interact with MHC class II molecules.

slide17

T LYMPHOCYTE MATURATION IN THE THYMUS

THYMIC

EPITHELIAL

CELL

TCR

CD8

MHC-peptide

CD4

TCR

T cells that bind Class I MHC-peptide complexes preserve expression of CD8 and lose CD4.

TCR

CD8

6. Negative and positive selection sorts out useful T lymphocytes from useless, or potentially dangerous T lymphocytes.

Thus, CD8 T cells develop on the basis of the ability of their TCR to interact with MHC class I molecules.

slide18

T LYMPHOCYTE MATURATION IN THE THYMUS

THYMIC

EPITHELIAL

CELL

MHC-peptide

T cells that do not recognize MHC molecules die by apoptosis (failure of positive selection).

CD4

TCR

CD8

TCR

6. Negative and positive selection sorts out useful T lymphocytes from useless, or potentially dangerous T lymphocytes.

This type of selection weeds out useless TCRs that are INCAPABLE of detecting MHC-antigen complex.

slide19

T LYMPHOCYTE MATURATION IN THE THYMUS

T cells that strongly bind MHC-peptide complexes die by apoptosis (negative selection).

TCR

6. Negative and positive selection sorts out useful T lymphocytes from useless, or potentially dangerous T lymphocytes.

THYMIC

EPITHELIAL

CELL

MHC-peptide

This type of selection deletes TCRs that detect self-antigens in complex with MHC molecules (removes autoreactive lymphocytes).

slide20

thymocyte maturation occurs in stages.

http://www.ag.uidaho.edu/mmbb/kgustin/mmbb409509/Lectures.html

slide21

Why this complicated system of positive and negative selection?

  • Positive selection gives MHC restriction but why?

Ensures that CD8+ T cells are specific for complexes of MHC class I with peptide and that CD4+ T cells are specific for MHC class II/peptide complexes.

2. Negative selection removes self-reactive cells.

slide22

Is antigen-presentation all that is needed?

What happens next?

The naive CD4 and CD8 T cells

migrate from thymus to peripheral

lymphoid organs to look for antigen

presented on MHC class I or II, then

they clonally expand.

slide23

The second signal comes from the

interaction of APC B7 with T cell

CD28.

Two signals are required to activate a naïve T cell.

slide24

T CELL SIGNALING - COSTIMULATORS

1. “Resting” APCs do not express costimulators, even though they may present peptide antigens to T cells.

2. Naïve T cells that encounter antigens in the absence of costimulators become anergic.

3. Microbes or innate immune cytokines stimulate expression of costimulators on APCs.

4. Costimulators are recognized by their receptors on T cells and provide the second signal necessary for T cell activation.

slide25

Not only does 1 signal not activate a naïve T cell,

it makes it anergic (unreactive).

Even if it goes to an APC

that can deliver the second

signal, it cannot be

activated.

Naïve cell:

1 signal

No killing or

activation

Anergy: A state of immune unresponsiveness. Induced when the T cell's antigen receptor is stimulated in the absence of a second signal.

slide26

Simultaneous detection of a foreign antigen and a second signal activates the T cell and drives subsequent immune responses.

Resting APCs express little or no co-stimulators and display self-antigens that are present in the tissue.

As a result the T cell becomes anergic and is no longer capable of mediating immune responses. Thus, anergy serves as an important safeguard against autoimmunity in the periphery.

Why?

slide27

Two signals are required to activate a T cell but only

one for the activated (mature) cell to function.

Naïve CD8 cell:

2 signals:

activated

Activated CD8 cell (CTL):

1 signal

kills.