Download B cell development, selection and maturation

2/19/2014
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
Bone marrow
PROGENITORS
SELECTION
ACTIVATION
EFFECTORS
periphery
B cell development: key concepts
1.
Lymphocytes derive from hematopoietic stem cells
2. B cell development begins by rearrangement of the heavy-chain locus
3. The pre-B-cell receptor (pBCR) tests for successful production of a
complete heavy chain
4. pBCR signals proliferation of late pro-B cells, “licenses” pre-B transit
5. 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 BM
2. If Immature B cells encounter self-antigen in the periphery, they are
eliminated or inactivated
B 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 locations
3. Terminal B cell differentiation: B cell => plasma cell
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STAGE ONE: GENERATION OF B CELLS
UNCOMMITTED
PROGENITOR
PRO B/PRE B
PRO-B/PRE-B
B CELL
THEME: SELECTION FOR “CORRECT” PROGRAM => Ig+ B CELL
Generation…
Multi-potent hematopoietic stem cells
generate all the cells of the immune system
??
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B cells develop in the bone marrow and then migrate to
secondary lymphoid tissues
Figure 4-2
In adults:
In
The early stages of B cell development are dependent
on bone marrow stromal cells
IL-7
Cell adhesion
becomes dispensable
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interactions between precursor B cells and stromal cells are required
for the development to the immature B-cell stage.
7.3
high-magnification electron micrograph
The “mission” of early
y B cell development
p
is to
generate the diverse repertoire of immunoglobulins:
Ig gene rearrangement is regulated and occurs in a
step-wise progression
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The development of a B-lineage cell proceeds through several stages
marked by the rearrangement and expression of Ig genes
MPP
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
surface markers
Ly6CDX5B220+
AA4+
LinIL7R+
CLP
CD19CD43+
HSAIL7R+
Pree p
pro-B
o
Fr A.
CD19+
CD43+
HSA++
CD43HSA++
IgM+
HSA++
BP-1+
pro-B
Fr B
pro-B/
l
large
pre-B
B
Fr C
pre-B
intracellular
+
Fr D
Immature
B
IgMLO
IgD+
HSA+
Mature
B
Fr E
R.R. Hardy JEM 1991 May 1;173(5):1213-25 and 2006 Mar 20;203(3):675-87.
further development of BM pro-B cells requires rearrangement and
expression of IgH chain gene
CLP
D-J
rearranging
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 recombination
is “sloppy” and many
junctions are made
that are in the wrong
reading frame; a minority
get it right
g and
of cells g
express IgH protein
VpreB and 5 are proteins
that form a complex with IgH
The pre-BCR acts a a quality control tester
Only 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-BCR
signaling
l
=> feedback
f db k
inhibition of IgH recombination
=> Small pre-B
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Note that rag expression
is 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 selfreactivity
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 lymphocytes
1) 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
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
Immature B cell
Rag expression continues
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VK REPLACEMENT
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Binding to self molecules in the bone marrow can lead to the death
or inactivation of immature B cells (CENTRAL TOLERANCE)
2
1
3
Immature B cell
Proliferate
+ effector functions!
mature B cell
Same Ag receptor; different outcomes
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STAGE THREE:
NEW B CELLS COMPLETE MATURATION, DISTRIBUTE, COMPETE
Terminal differentiation of B cells
TR= transitional immature B cell
Nature reviews IMMUNOLOGY 2:323-335 2002
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B cell development continues in the peripheral lymphoid tissues
Peritoneum
And..
omentum
Mouse Mature B lymphocyte Populations
B-2 Follicular: IgMLo IgDhi CD23hi CD5Marginal Zone B: IgMhi IgDLo CD23- CD5- CD21hi
B-1
B-1a: IgMhi IgDdull CD23-/lo Mac1+CD5+
B-1b: “
Spleen
l
B2
MZB
“
“
CD5-
“
L
Lymph
h Nodes,
N d
Peyer’s
P
’ Patch
P
h
P i
Peritoneal,
l
Pleural, Mucosal
B2
B1a
CD5+B1a
CD5+B1a
B1b
B2
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n
Spleen organization
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
Proposed population dynamics of conventional B cells
Peripheral
tolerance
First, the spleen
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
y arrived in spleen
p
can
be 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
• further
f th maturation
t
ti occurs in
i the
th spleen
l
• 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 CD5Marginal Zone B: IgMhi IgDLo CD23- CD5- CD21hi
B-1
B-1a: IgMhi IgDdull CD23-/lo Mac1+CD5+
B-1b: “
Spleen
l
B2
MZB
“
“
CD5-
“
L
Lymph
h Nodes,
N d
Peyer’s
P
’ Patch
P
h
P i
Peritoneal,
l
Pleural, Mucosal
B2
B1a
CD5+B1a
CD5+B1a
B1b
B2
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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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Nature reviews IMMUNOLOGY 2:323-335 2002
Differential kinetics of innate and adaptive
immune responses in vivo
Development and differentiation of
B cells
Nature reviews IMMUNOLOGY 2:323-335 2002
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Long-lived plasma cells
reside 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
p
g
proliferation
p
of late pro-B
p
cells, enforces allelic exclusion
•
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 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
27