B-Cell Development, Activation, and Differentiation, Study notes of Immunology

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B-Cell Development, Activation,

and Differentiation

Sarah Holstein, MD, PhD

Nov 13, 2014

Lymphoid tissues

• Primary

– Bone marrow

– Thymus

• Secondary

– Lymph nodes

– Spleen

– Tonsils

– Lymphoid tissue within GI and respiratory tracts

Overview of B cell development

• Early B cell development constitutes the steps that lead to B cell commitment and expression of surface immunoglobulin, production of mature B cells
• Mature B cells leave the bone marrow and migrate to secondary lymphoid tissues
• B cells then interact with exogenous antigen and/or T helper cells = antigen- dependent phase

Overview of B cells

Role of bone marrow stromal cells

• At various points

in development,

progenitor and

precursor B cells

interact with

specific stromal

cell populations

secreting specific

cytokines

HSCs

• Self-renewing,

multipotential

• Give rise to all blood cells
• Depending on stimuli

received, different

transcription factors can

drive HSCs down different

developmental pathways

• Ikaros, PU.1 and E2A are

all important transcription

factors for B cell fate

• Express cKit (CD117)

(receptor for stem cell

factor)

LMPPs (lymphocyte primed

multilineage progenitors)

• Express flt-3 (binds to

flt-3 ligand on BMSCs), leading to IL-7 receptor synthesis

• Flt-3 expression marks

loss of MPP to develop into red blood cells or megakaryocytes, but still can differentiate into myeloid or lymphoid

ELPs (early lymphoid progenitors)

• Express RAG1/

(recombination

activating genes)

• Some migrate to

thymus, remainder

stay in the marrow as

B cell progenitors

Immunoglobulin gene rearrangements

and B cell development

• During early stages of B cell development, functional

rearrangements of the heavy chain gene locus (IgH)

allows for assembly of the pre-B cell receptor

complex  cessation of IgH rearrangements (allelic

exclusion)  light chain rearrangements (kappa,

then lambda)

• Production of complete Ig (2 heavy chains, 2 light

chains) allows for assembly of mature B cell receptor

on the cell surface  signals cessation of light chain

gene rearrangement  mature B cell stage

Pre-Pro B cells

• Express CD45R, a B-cell lineage-specific

marker

• Increase expression of EBF-

• EBF-1 and E2A bind the Ig gene, promoting

accessibility of D-JH locus, preparing for the 1 st

step in Ig gene recombination

• EBF-1 also important for expression of other B

cell proteins, including CD79α/β and genes

encoding the pre-B cell receptor

Pre B cells

• Ig heavy chain genes complete V-D-J recombination
  • Allows surface expression of Ig heavy chain and surrogate light chains complex = pre-B cell receptor
• CD79a and CD79b (Ig-α and Ig-β)
  • associate non-covalently with surface Ig
  • signal transducing components of the pre-B cell receptor
  • also components of the Ig receptors on the surface of mature B cells
• Signaling through the pre-B cell receptor induces a few rounds of proliferation; at the end of this the pre-B cell receptor is lost from the surface  late pre B cell stage
• If pre B cell receptor cannot be displayed on cell surface because of nonproductive VHDJH gene rearrangement, then B cell development stops and the cell undergoes apoptosis (1st^ checkpoint)
• Pre-B cell receptor signaling causes transient decrease in RAG1/2 and loss of Tdt
• Ensures that as soon as one heavy chain gene has been rearranged, no further recombination is possible (allelic exclusion)
• Light chain rearrangement is initiated following re-expression of RAG1/
• Once light chain rearrangement has been successfully completed, the intact IgM receptor can be expressed - If light chain rearrangement does not occur successfully, then the 2nd^ checkpoint occurs

Immature B cells

• Have functional IgM but no other Ig expression
• Express B220, CD25, IL-7R, CD
• Once there is a functional BCR on the membrane, it has to be tested for its ability to bind self-antigens to ensure that few auto-reactive B cells are released
• Three fates if autoreactive
  • Clonal deletion via BCR-mediated apoptosis
  • Reactivation of RAG to initiate process of light chain receptor editing
  • Survive and escape the BM but become anergic
• B cell loss prior to leaving the BM = central tolerance
• Export to spleen where further development occurs
• Very susceptible to tolerance induction

T1 and T2 transitional B cells

• T1: mIgMhi^ , mIgD -/lo, CD21-, CD23-, CD24+, CD93+
• T2: higher levels of mIgD, CD21+, BAFF-R
• T1 T2  mature B cells
• Most T1 transitional B cells differentiate to T2 within the spleen but ~25% of T emerge directly from the BM
• T2 cells capable of recirculating among the blood, lymph nodes, spleen
• T2 cells can enter B cell follicles

T1 and T2 transitional B cells

• Self-reactive T1 B cells

eliminated by apoptosis in

response to strong antigenic

signal (peripheral tolerance)

• 55-75% of immature B cells lost this way
• T2 cells become resistant to antigen-induced apoptosis
• Increased Bcl-X1 expression
• BAFF receptor expression

first detected in T1 B cells,

increases thereafter

• Promotes survival of transitional B cells