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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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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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
Nature reviews IMMUNOLOGY 5:606-616 2005
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
Nature reviews IMMUNOLOGY 2:323-335 2002
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
Nature reviews IMMUNOLOGY 2:323-335 2002
Development and differentiation of B cells
Nature reviews IMMUNOLOGY 2:323-335 2002
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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