B and T Lymphocyte Development

The process of making the genes that code for the receptor subunit proteins of B and T cells is...

completely random

Where does B cell development occur?

bone marrow

Where do T cells develop?

thymus

What is B cell development dependent upon?

successful BCR gene rearrangements

Each B cell that makes it through development has a unique ___________________ with a unique ___________________

receptor, specific antigen specificity

Stages in B cell development are identified by...

surface proteins that are expressed

AND

the arrangements of Ig genes

What is the earliest identifiable cell of the B cell lineage?

Pro-B cell

What does it mean to be a pan cell marker? What are the pan cell markers?

expressed on all B cells, CD19 and CD20

Hematopoietic stem cells are CD________

34

When are pan B cell markers seen?

Pro B cell stage

Stages of B cell development

pro B cell

pre B cell

immature B cell

mature B cell

Pro B cell

DNA is spliced to create the mu heavy chain gene

(creates the IgM heavy chain protein)

Pre B cell

DNA is spliced to create the light chain genes (kappa or lambda) while the pre-BCR is expressed

Immature B cell

Stage of B cell with IgM expressed on surface

What occurs in the immature B cell stage in addition to IgM being expressed on the surface?

Testing for self-reactivity

Immature B cells that are not ______________ can leave the ______________

self-reactive, bone marrow

Mature B cells

complete development in secondary lymphoid tissues and express both IgM and IgD

What is critical for B cell maturation?

interactions with bone marrow stromal cells and their production of SCF and IL-7

these are cytokines

Checkpoints ensure that the IgM heavy chain that is randomly created is...

functional and not self reactive

The checkpoint to ensure IgM is functional makes sure that it...

can pair with the pre-BCR and the signaling molecules IgA and IgB to send activation signals

can pair with the randomly made light chain

When is pre-BCR introduced to the two heavy mu chains?

pre-B cell stage

When a heavy chain and light chain are paired, the antigen binding site that is formed is tested for

self-reactivity

When the mu heavy chain is made, it is paired with a _______________ to stabilize it and see if it can interact with the signaling molecules ___________________

pre-B cell receptor, IgA and IgB

*occurs in the pre-B cell stage

If the mu heavy chain can interact with the pre-BCR and can send signals to IgA and IgB, what happens next?

the B cell begins making the light chain

Allelic exclusion

only one heavy chain and one light chain are produced in each B-cell

Once the IgM heavy chain is made and tested, what happens to the rearrangement of the mu gene segments on the other chromosomes?

they are turned off

At what stage are B cells tested by binding to antigen produced stromal cells for self-reactivity?

immature stage

Because B cells make the genes for BCR randomly, it is possible that the antigen binding site will bind...

Self antigen

Bone marrow stromal cells express ____________ genes that are produced by what cell types?

Housekeeping, all body cell types

If the BCR binds self antigen strongly enough to activate signaling, then the B cell is/isn't self reactive?

Is

If the B cell is self reactive, what has to happen?

It has to go through receptor editing to change its light chain

If a B cell is self reactive, it can only edit what?

Light chain only

B cells that pass testing for self-reactivity can leave the bone marrow and go where?

To secondary lymphoid tissue where they continue to mature

Mature B cells express what?

Both IgM and IgD

Follicular cells

Classic B cells that form germinal centers

Marginal zone B cells

Migrate to the marginal zone of the spleen and produce low affinity antibodies that can differentiate into short lived plasma cells

What is the only B cell to express two different classes of antibodies?

Mature B cell

T cells with TCRs made of an alpha and beta subunit are...

Classic T cells

Gamma delta T cells bind what?

Lipids presented by CD1 molecules

T cell development is linked to the rearrangement of...

TCR genes

Are T cells made in response to any specific pathogen or foreign molecule?

No

Interactions with what are critical for thymocyte development?

Stromal cells and signals from the factors they secrete

What are the factors that stromal cells secrete?

SCF (stem cell factor) and IL-7

When is the human thymus fully developed? What happens around a year after birth?

Before birth, it degenerates

DiGeorge syndrome

The thymus fails to develop. T cells are absent and patients basically have no immune system

Thymocyte stages

Double negative (CD4/8-)

Double positive (CD4/8+)

Single positive (CD4+ or CD8+)

When AB rearrangements fail, what T cells can be developed?

DG

Positive selection occurs when in thymocyte development?

Double positive stage

What is tested in the positive selection of thymocyte?

The ability of the TCR to interact with self (host) MHC molecules

Having both CD4 and CD8 expressed means that the TCR can interact with...

MHC 1 or 2

What determines whether the thymocyte keeps CD4 or CD8?

Whether it interacts with MHC I or II

When does negative selection occur in thymocyte development?

Single positive stage

What does negative selection test for?

The affinity of the TCR for self antigen

In negative selection, thymocyte are deleted when?

When the TCR binds host peptides or has too strong of an affinity for host MHC

AIRE

Transcription factor autoimmune regulator

What does AIRE do?

Turns on the expression of host cell genes in thymocyte epithelial cells

Why does AIRE turn on these host cell genes?

To expose thymocyte to self-proteins so negative selection can be more effective

In the absence of AIRE, thymocyte are not properly selected and a myriad of autoimmune manifestations result, which are collectively referred to as...

APECED or APS-1

Thymocyte that pass what selection are considered mature and released from the thymus?

Positive and negative selection

Do T cells undergo further maturation after release? Do B cells?

T cells do not, B cells can

How long are B and T cells produced?

B cells are for life, constantly

T cell production decreases around puberty, thymus decreases size

How are TCRs generated?

Randomly