B cell activation

There are two types of B cell activation, requiring or not interaction with CD4+ T cells:

• thymus-dependent activation
  This is the conventional pathway of B cell activation described in this chapter. It requires interaction with a previously activated CD4+ T cell.
• Thymus-independent activation
  This pathway mainly concerns B cells in the marginal zone of the spleen. It does not require interaction with CD4+T cells , and sometimes even no recognition by the BCR. The antigens leading to these activations are very generally microbial and lead to the genesis of short-lived IgM plasmablasts , but do not lead to the synthesis of memory B cells or class switching.
  Thymus-independent activation mechanisms are not described here because they are poorly represented in alloreactivity.

B cell

BCR

CD4+
T cell

Antigen

Secondary
lymphoid
organs

Cytokines

Where?

In the B cell zone of the secondary lymphoid organs, which constitutes a zone of concentration of antigens:

• In the lymph nodes: the cortical zone

Organisation of a lymph node

• In the spleen : within the white pulp, in the primary and secondary follicles

Organisation of the white pulp of the spleen

When?

After having undergone central selection in the bone marrow, then peripheral in the blood and in the spleen in order to eliminate auto-reactive B cells (see B cell ontogeny), B cells circulate in the bloodstream and enter secondary lymphoid organs.
They are looking for the antigen that could be recognised by their BCR. If a B cell recognises a native antigen corresponding to its BCR, this constitutes its first activation signal.

How is this done?

Thymus-dependent activation of a B cell requires two signals. This mode of activation affects the vast majority of protein antigens, including those involved in organ transplantation. The activation is called conventional, and involves B cells to allow them to ultimately differentiate:

• either into short-lived plasmablasts producing IgM with low affinity for the antigen. This is the primary immune response;
• or into B cells hat are founders of germinal centres, which will differentiate into memory B cells or long-lived plasma cells. This is the secondary immune response.

DC = dendritic cell, BC = B cell, TC = T cell

The engagement of at least two BCRs of the same B cell results in the formation of a bridge necessary for signal transduction by CD79 associated with the BCRs. The downstream pathway is initiated by the phosphorylation of the ITAM motifs of the CD79 chains, which will induce the expression of chemokine receptors on the surface of the B cell, and thus promote the migration of the B cell into the T/B cooperation zone of the secondary lymphoid organs.

In parallel, the antigen is internalised and processed to be presented via a Class II HLA molecule.

The B cell behaves like a professional antigen-presenting cell by presenting the antigen previously recognised by its BCR, then internalised, via its Class II HLA molecules. The follicular CD4+ T cell previously activated and having migrated into the follicular zone of the lymph node will recognise the complex [peptide – Class II HLA molecule] via its TCR.

Following this interaction, the CD4+ T cell expresses CD28and secretes interleukins, which will allow the B cell to continue its maturation towards transformation into a plasma cell or memory B cell.

Interactions between the CD4+ T cell and B cell promote:

• education of germinal centres

The germinal centre is a substructure dedicated to the generation of B cell clones expressing immunoreceptors (BCR) with very high affinity for an antigen.
A germinal centre develops at the expense of the follicular zone, whether in the spleen or in the lymph node. The appearance of a germinal centre signals the transition from a primary follicle to a secondary follicle.

• Somatic hypermutation of the BCR

The B cell clone engaged in the formation of a germinal centre proliferates and undergoes somatic hypermutations of the genes encoding the BCR variable region thanks to an enzyme called AID (Activation-Induced Cytidine Deaminase). The follicular dendritic cells present in the environment present the antigen to them continuously to test the affinity of the new receptor towards the antigen :

• if the new BCR has better affinity, then the B cell survives and differentiates into a plasma cell or a memory B cell;
• if, on the contrary, the BCR has a lower affinity, then the clone degenerates.

• Class switching

B cells initially express only membrane IgM or IgD (see B cell ontogeny). The interaction with the CD4+ T cell, as well as the cytokine environment within the secondary follicle modifies the cellular programming of the B cell (notably the splicing programs), which makes it possible to modify the isotype of the immunoglobulins secreted by the plasma cell (IgM ➔ IgG, IgA or IgE).

• Differentiation of B cells into long-lived plasma cells

The interaction of the CD4+ T cell directs the B cell response towards the genesis of long-lived plasma cells and memory B cells.

In organ transplantation, the inhibition of B cell activation is mainly achieved indirectly, through the inactivation of helper T cells. Drugs specifically targeting the B cell lineage are anti-CD20 monoclonal antibodies and proteasome inhibitors that deplete B cells and plasma cells, respectively.