b cell’s main effector function: secrete antibodies!...2/19/2014 1 b cell development, selection...

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B cell development, selection and maturation

2/18/14

Rachel Gerstein

Dept MaPS

B cell’s main effector function: secrete antibodies!

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PC = plasma cell. Aka antibody secreting cell (ASC)

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Lymphocyte receptors - B cells

membrane-bound versions of antibodies

Larry Stern

clonal selection of lymphocytes

Note: each cell has only one specificity - only one form of the receptor

Larry Stern

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The life-cycle of a B lymphocyte

GENERATION SELECTION ACTIVATION EFFECTORS

peripheryBone marrow

B cell development: key conceptsPROGENITORS

1. Lymphocytes derive from hematopoietic stem cells2. B cell development begins by rearrangement of the heavy-chain locus3. The pre-B-cell receptor (pBCR) tests for successful production of a

complete heavy chain4. pBCR signals proliferation of late pro-B cells, “licenses” pre-B transit5. Pre-B cells rearrange the Ig light chain loci

IMMATURE B CELLS

1. Immature B cells are tested for auto-reactivity before they leave the BM2. If Immature B cells encounter self-antigen in the periphery, they are

eliminated or inactivated

B CELL SUBSETS AND EFFECTOR CELLSB CELL SUBSETS AND EFFECTOR CELLS

1. Immature B cells arriving in the spleen are short-lived and require cytokines and BCR signals for maturation and survival

2. Different lymphocyte subsets are found in particular locations3. Terminal B cell differentiation: B cell => plasma cell

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STAGE ONE: GENERATION OF B CELLS

UNCOMMITTED PRO B/PRE BB CELLUNCOMMITTED

PROGENITORPRO-B/PRE-B

THEME: SELECTION FOR “CORRECT” PROGRAM => Ig+ B CELL

Multi-potent hematopoietic stem cellsgenerate all the cells of the immune system

Generation…

??

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Figure 4-2

B cells develop in the bone marrow and then migrate to secondary lymphoid tissues

In adults:

In

The early stages of B cell development are dependent on bone marrow stromal cells

IL-7

Cell adhesionbecomes dispensable

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interactions between precursor B cells and stromal cells are requiredfor the development to the immature B-cell stage.

7.3

high-magnification electron micrograph

The “mission” of early B cell development is to y pgenerate the diverse repertoire of immunoglobulins:

Ig gene rearrangement is regulated and occurs in a step-wise progression

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MPP

The development of a B-lineage cell proceeds through several stages marked by the rearrangement and expression of Ig genes

CLP/pre-pro-B

Note: this has corrections to the Janeway figure Also covered by Stavnezer

Expression of surface proteins in B cell development

Note: this has corrections to the Janeway figure

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B cell development classification using B cell development classification using surface markerssurface markers

B cell development classification using B cell development classification using surface markerssurface markers

Ly6C-

CD43+HSA++

pro-B

B220+

CLP

AA4+

Lin-IL7R+

CD43+HSA-

Pre- pro-B

CD43-HSA++

pre-Bintracellular

HSA++IgM+

Immature

CD19- CD19+

DX5-

MatureB

HSA+

IgMLO

IgD+IL7R+

pro-B/l B

BP-1+

e p o+

intracellular B

Fr A. Fr B Fr D Fr EFr C

large pre-B

R.R. Hardy JEM 1991 May 1;173(5):1213-25 and 2006 Mar 20;203(3):675-87.

CLP

further development of BM pro-B cells requires rearrangement and expression of IgH chain gene

D-Jrearranging

Note: this has corrections to the Janeway figure

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A productively rearranged immunoglobulin gene is immediately expressed as a protein by the developing B cell

V(D)J recombinationis “sloppy” and manyjunctions are madethat are in the wrongreading frame; a minorityof cells get it right and g gexpress IgH protein

VpreB and 5 are proteinsthat form a complex with IgH

The pre-BCR acts a a quality control testerOnly pre-B cells with a “good” H chain proceed

www.allposters.com/-sp/Quality-Control-Posters_i420258_.htm

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What does the pre-BCR “tell” the pre-B cell ?

Proliferates!

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Allelic exclusion in individual B cells

A consequence of pre-BCRl f db ksignaling => feedback

inhibition of IgH recombination

=> Small pre-B

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Note that rag expressionis retained in Imm B cell

Non-productive light chain rearrangements can be rescued by further gene rearrangement (receptor editing)

small pre-B cell

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This capacity to replace a rearranged Vk-Jk exon with a new exon is also used to replace light chains that confer self-reactivity

This process is called receptor editing and is an essential mechanism of tolerance

Note:

defects in tolerance = self-reactivity => auto-immune disease

Once the initial Ig repertoire is formed, it is subject to selection and revision

This is essential for tolerance to self

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Figure 4-1 part 1 of 2

Tolerance:•critical process to avoid auto-immune disease

•Imperfect !

STAGE TWO: SURFACE Ig+ IMMATURE B CELLS

UNDERGO FURTHER MATURATION

THEME ONE: TOLERANCE

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Steps in the clonal selection of lymphocytes1) Make a lot of receptors

Note: each cell has only one specificity - only one form of the receptor

Larry Stern

Steps in the clonal selection of lymphocytes

2) Pick one that works

•does not react with self

• release cells to • release cells to blood to join pool of circulating lymphocytes

Larry Stern

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There are several distinct mechanisms of B cell tolerance

Larry Stern

1 = RECEPTOR EDITING

Rag expression continues

Immature B cell

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VK REPLACEMENT

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Binding to self molecules in the bone marrow can lead to the deathor inactivation of immature B cells (CENTRAL TOLERANCE)

121

3

Immature B cell

mature B cell

Proliferate+ effector functions!

Same Ag receptor; different outcomes

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STAGE THREE:

NEW B CELLS COMPLETE MATURATION, DISTRIBUTE, COMPETE

Terminal differentiation of B cells

Nature reviews IMMUNOLOGY 2:323-335 2002

TR= transitional immature B cell

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B cell development continues in the peripheral lymphoid tissues

PeritoneumAnd..omentum

Mouse Mature B lymphocyte Populations

B-2 Follicular: IgMLo IgDhi CD23hi CD5-

Marginal Zone B: IgMhi IgDLo CD23- CD5- CD21hi

B-1B-1a: IgMhi IgDdull CD23-/lo Mac1+CD5+

B-1b: “ “ “ “ CD5-

l P i l L h N d P ’ P h

B2

CD5+B1a

MZB

B1aB1b

B2

Spleen Peritoneal, Pleural, Mucosal

B2

CD5+B1a

Lymph Nodes, Peyer’s Patch

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Spleen organizationn

Peri-arteriolar lymphoid sheath PALS


The normal architecture of the peripheral lymphoid organs requires TNF family members and their receptors

(Stromal)

Needed for follicle to develop

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Generation of mature B cells requires BLyS

TR= transitional immature B cell


First, the spleen

Proposed population dynamics of conventional B cells

Peripheral tolerance

imm

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Competition for entry into the primary B cell follicle

• MANY newly generated B cells are auto-reactive

• Immature B cells recently arrived in spleen can y pbe easily tolerized by encounter with self antigen

• these B cells are called transitional B cells

• peripheral tolerance occurs by either deletion or anergy• anergic B cell cannot enter follicle;• there is active competition for entry

f th t ti i th l• further maturation occurs in the spleen

• only mature B cells enter the follicle

• mature follicular B cells are long-lived and circulate

Mouse Mature B lymphocyte Populations

B-2 Follicular: IgMLo IgDhi CD23hi CD5-

Marginal Zone B: IgMhi IgDLo CD23- CD5- CD21hi

B-1B-1a: IgMhi IgDdull CD23-/lo Mac1+CD5+

B-1b: “ “ “ “ CD5-

l P i l L h N d P ’ P h

B2

CD5+B1a

MZB

B1aB1b

B2

Spleen Peritoneal, Pleural, Mucosal

B2

CD5+B1a

Lymph Nodes, Peyer’s Patch

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A comparison of the properties of B1 cells, B2 cells and marginal zone B cells

Some*

(*Revision of the Janeway figure)

B cell subpopulations(B1 cells are in body cavities and GUT)

CURR OP IMM 13:195-201 2001

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Differential kinetics of innate and adaptive immune responses in vivo


Development and differentiation of B cells


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Long-lived plasma cellsreside in the BM.

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B cell development

PROGENITORS• Lymphocytes derive from hematopoietic stem cells• B cell development begins by rearrangement of the heavy-chain locus• The pre-B-cell receptor (pBCR) tests for successful production of a

complete heavy chain• pBCR signals proliferation of late pro-B cells, enforces allelic exclusionp g p p• Pre-B cells rearrange the Ig light chain loci

IMMATURE B CELLS• Immature B cells are tested for auto-reactivity before they leave the

BM• Lymphocytes that encounter self-antigen for the first time in the

periphery are eliminated or inactivated

B CELL SUBSETS AND EFFECTOR CELLSB CELL SUBSETS AND EFFECTOR CELLS• Immature B cells arriving in the spleen are short-lived and require

cytokines and BCR signals for maturation and survival• Different lymphocyte subsets are found in particular locations• Terminal B cell differentiation: B cell => plasma cell

b cell’s main effector function: secrete antibodies!...2/19/2014 1 b cell development, selection...

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