Lecture 12 - B lymphocyte biology and effector functions II

Why do transitional B2 cells require T cell help for survival and activation?

BCR signalling alone is insufficient. Full activation requires:

• Antigen presentation via MHC II

• Help from CD4⁺ T cells, especially T_FH cells → enables class switching, affinity maturation, and memory formation

What is the mechanism by which B cells present antigen to CD4⁺ T cells?

1. BCR binds antigen → internalizes via receptor-mediated endocytosis

2. Antigen processed in endosomes → peptides loaded onto MHC II

3. pMHC II traffics to surface → recognized by TCR on CD4⁺ T cells

What three signals do B cells provide to CD4⁺ T cells?

1. Signal 1: pMHC II → TCR binding

2. Signal 2: CD80/CD86 → CD28 costimulation

3. Signal 3: Cytokines → influence T cell differentiation

What changes occur in B cells after BCR engagement?

• Upregulation of MHC II

• Increased CD80/CD86 co-stimulatory molecules

• Secretion of cytokines (e.g., IL-4, IL-6)

How did Crawford et al. (2006) confirm that B cell antigen presentation is essential?

Using mixed bone marrow chimeras with MHC II-deficient B cells, they showed impaired CD4⁺ T cell activation, despite normal DCs/macrophages → proves B cells are not redundant APCs

What clinical therapy targets B cells and what does it reveal about their function?

Rituximab (anti-CD20) depletes B cells (not plasma cells).
Used in RA and SLE.
Improvement without major drop in antibodies → suggests APC function, not just antibody production, drives disease.

How do B cells extract membrane-bound antigen?

Via cytoskeletal remodeling, actin-dependent spreading, and immune synapse formation → extract Ag from:

• APCs (e.g., DCs/macrophages)

• Subcapsular macrophages

• Extracellular matrix (ECM) components (e.g., cartilage)

Why is BCR-mediated uptake more efficient than pinocytosis?

Because it is antigen-specific, concentrating low-abundance antigens for focused processing and MHC II presentation.

What are the consequences if B cells do not present antigen to T cells?

• No class switching (CSR)

• No somatic hypermutation (SHM)

• Only short-lived IgM⁺ plasma cells are generated
  → Poor memory, low-affinity antibody response

How do cytokine profiles differ between DCs and B cells?

• DCs: High IL-6 → promote Th1 and Th17

• B cells: Low IL-6 → may favour Th2 or regulatory responses

How did Barr et al. (2011) demonstrate the role of B cell-derived IL-6?

IL-6 deletion in B cells → reduced Th17 responses and EAE severity.
Anti-CD20 therapy in MS also reduces IL-6 levels.

What are Bregs and what cytokine do they produce?

Regulatory B cells (Bregs) produce IL-10 → suppress excessive immune responses, promote resolution in autoimmunity models like EAE and arthritis.

What key references support the role of B cells as APCs?

• Lanzavecchia et al. (1988): BCR-mediated uptake enhances APC efficiency

• Chan & Shlomchik (1998): B cells activate CD4⁺ T cells in vivo

• Yan et al. (2006): B cells activate T cells faster than DCs

What is the role of surface antigen vs soluble antigen in B cell activation?

Membrane-bound antigens (e.g., ECM, APCs) are preferentially acquired by B cells using mechanical force and immune synapse formation → enhances T–B interaction

How do B cells promote linked recognition with T cells?

B cells present peptides derived from antigens they bind via BCR → ensures T cells help only cognate, specific B cells, enhancing precision and safety.

What is the key cytokine produced by regulatory B cells (Bregs)?

IL-10 — suppresses immune responses and inflammation in models like EAE and collagen-induced arthritis.

Which studies demonstrated the suppressive function of Bregs?

Fillatreau et al. (2002) and Evans et al. (2007): Bregs produce IL-10, suppress T cell responses, and promote recovery in autoimmune disease models.

What role do Bregs play in controlling autoimmunity?

• Limit pathogenic T cell responses

• Suppress inflammation

• Facilitate immune resolution in diseases like EAE and CIA

Which cytokine is more abundantly produced by DCs than B cells, influencing Th differentiation?

IL-6 — higher in DCs, promotes Th1 and Th17; lower in B cells, possibly favouring Th2 or tolerance.

What did Barr et al. (2011) demonstrate about B cell-derived IL-6?

B cell–specific IL-6 deletion → reduced Th17 responses and EAE severity, showing IL-6's role in autoimmune pathology.

How does anti-CD20 therapy (e.g., Rituximab) affect cytokine levels in MS patients?

Reduces IL-6 levels, indicating B cell contribution to inflammatory cytokine production in disease.

What experiment showed that B cells extract antigen from surfaces using cytoskeletal remodeling?

Batista & Neuberger (1998); Fleire et al. (2006): B cells extract membrane-bound antigen via actin-dependent spreading and contraction.

What is the biological relevance of B cells presenting membrane-bound antigens?

• Ensures focused uptake

• Promotes efficient linked recognition

• B cells access Ags from APCs, subcapsular macrophages, and ECM

What distinguishes B cell Ag acquisition from dendritic cells?

• B cells: Prefer membrane-bound Ag, use immune synapse

• DCs: Capture soluble and particulate Ag via pinocytosis and phagocytosis

Which experimental approach confirmed that only B cells were deficient in MHC II while other APCs remained intact?

Crawford et al. (2006) used mixed bone marrow chimeras where only B cells lacked MHC II → impaired CD4⁺ T cell activation.

What evidence showed B cells can activate self-reactive T cells in vivo?

Lin (1991): Antigen-specific B cells transferred into tolerant mice activated self-reactive CD4⁺ T cells.

What did Yan, Shlomchik & Mamula (2006) discover about B vs DC APC efficiency?

Ag-specific B cells activated CD4⁺ T cells faster than DCs in adoptive transfer experiments.

Why is antigen presentation by B cells essential for class switching and affinity maturation?

Because CD4⁺ T cell help via pMHC II recognition is needed for:

• Class switch recombination (CSR)

• Somatic hypermutation (SHM)

• Memory and plasma cell generation

What is the key difference in IL-6 production between B cells and DCs?

• DCs: Produce more IL-6 → support Th17/Th1 differentiation

• B cells: Produce less IL-6, may bias toward Th2 or tolerance