asilmi 08 - t cell development today t lymphocyte development

Asilmi 08 - T CELL DEVELOPMENT

TODAY

T LYMPHOCYTE DEVELOPMENT


THE T CELL RECEPTOR (TCR)

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

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.

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


The TCR compared with a free Ig molecule.

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.


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.


AgAg

2

1

2

3

MHC I

ANATOMY OF AN MHC-PEPTIDE-TCR COMPLEX

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

Ag

2

1

2

3

V

V

MHC I

TCR

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

3. Additional TCR residues interact with the MHC molecule.


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

T Ag are linear molecules in the context of MHC

Tc : CD8Th : CD4

TCRTCR

APCAPC

CD8CD4

TCR CD8

MHC I

TCR

MHC II

CD4


THE TCR INTERACTS WITH THE PEPTIDE AND THE MHC

CD4 and CD8 do NOT interact with the antigenic peptide.

antigenantigen

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

antigen

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.


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.


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.


What a T cell recognizes in an ‘antigen’is a unique combination of MHChaplotype and peptide with therecognition assisted by either CD4 orCD8.

The end result: a naïve CD4 or CD8 T cellthat recognizes a 3 dimensional surface comprised

of both peptide and MHC.


FEATURES OF TCR-MEDIATED ANTIGEN RECOGNITION

4. Signaling triggers T lymphocyte activation.

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

2. Each clone is specific for a single antigen.

1. TCR recognize peptides presented by MHC molecules.


TCR proteins on different T cells arise from gene rearrangement of multiple germ line genes (just like BCR gene rearrangement).

The beta chain gene isformed from differentV, D, J, and C generecombination.

During T cell developmentalpha chain V, J and Cgenes recombine toform the T cell alpha genethat characterizesthat T cell.


ALLELIC EXCLUSION

MATERNALV CJ

PATERNALV CJ

Each individual inherits maternal AND paternal alpha chain genes.

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

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.


TCR rearrangement occurs in the thymus.

T cell progenitors (thymocytes) migrate from bone marrow tothe thymus.

1

TCR genes rearrange in the thymus toproduce T cells, which then migrate toperipheral lymphoid organs to find antigen

2


T LYMPHOCYTE MATURATION IN THE THYMUS

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

THYMICEPITHELIALCELL

MHC-peptide

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

TCR

Positive selection

TCR

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


CD4TCR

CD8

TCR



MHC-peptide

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

CD4TCR

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



CD8

CD4TCR

TCR



MHC-peptide

CD8TCR

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

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



TCR

TCR

CD4

CD8

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



MHC-peptide

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




MHC-peptide

TCR

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



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


thymocyte maturation occurs in stages.

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

QuickTime™ and aYUV420 codec decompressor

are needed to see this picture.


Why this complicated system of positive and negative selection?

1. 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.


The naive CD4 and CD8 T cellsmigrate from thymus to peripherallymphoid organs to look for antigenpresented on MHC class I or II, then they clonally expand.

Is antigen-presentation all that is needed?

What happens next?


Two signals are required to activate a naïve T cell.

The second signal comes from theinteraction of APC B7 with T cellCD28.


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.

T CELL SIGNALING - COSTIMULATORS


Not only does 1 signal not activate a naïve T cell,it makes it anergic (unreactive).

Naïve cell:1 signalNo killing oractivation

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

Even if it goes to an APCthat can deliver the secondsignal, it cannot be activated.


Why?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.


Two signals are required to activate a T cell but onlyone for the activated (mature) cell to function.

Naïve CD8 cell:2 signals:activated

Activated CD8 cell (CTL):1 signalkills.

asilmi 08 - t cell development today t lymphocyte development

Documents