Cell Surface Molecules that Regulate B cell Responses

A physical interaction between B and Th cells has long been recognised to be vital in antibody responses (279). A number of experimental studies demonstrated the requirement for contact-mediated signals in which resting B cells stimulated with fragments from activated T cell membranes or T cell associated molecules became activated and could proliferate (22,23,47,296,361). Full B cell activity, however, measured by the synthesis of mature immunoglobulin transcripts and immunoglobulin secretion, required further cytokine-mediated signals (187,295,298). These

observations underline the mutual importance of both cognate and soluble factors in Th-B interactions.

Some of the molecules involved in Th-B interactions are constitutively expressed, for example, CD40 on B cells and CD28 on Th cells, although their expression is increased upon activation. Each receptor-ligand pair does not act in isolation but as a cascade o f bi-directional signals resulting in the reciprocal dialogue between B, Th and accessory cells that is essential for the precise regulation o f the response (84). In some cases there are well defined receptor-ligand pairs e.g. CD40 and CD40L, while others are still 'searching' for a ligand e.g.CD20 and CD 19. Major cell surface molecules that are expressed on activated B and Th cells and which merit a brief description here are the B7 family and their counterparts CD28 and CTLA-4, CD21 and CD23, GDI la/18 (LFA-1) and CD54, CD58 (LFA-3) and CD2, CD72 and CD5, Finally I will focus on the CD40 and CD40L receptor-ligand pair.

1.5.1. The B7 family, CD28 and CTLA-4

Th cells activated through the TcR by antigen require further stimulation via CD28. This regulates IL-2 expression and prevents T cell anergy and unresponsiveness to further stimulatory signals (209). In addition IL-4 production is increased and T cell proliferation is enhanced. The absence of a CD28-mediated signal leads to impaired immune function in vitro and in vivo. CTLA-4 has 75% nucleotide sequence with CD28 and its transient expression is detected 2-3 days following T cell activation. CD28 and CTLA-4 both bind B7-1/BB1 and B7-2/B70 (CD80 and CD86 respectively) (141,176,362) expressed on activated B cells (238). B7-2 is an early activation antigen expressed rapidly following B cell activation (92,142). B7-1

expression occurs much later, after approx. 24-48hrs. CD28-cross-linking is likely to have a positive feedback effect in the regulation of T-dependent B cells responses as stimulation enhances CD40L expression (223) which in turn can enhance CD80 expression (426). The role o f CTLA-4, was less clear but CTLA-4-deficient mice have been found to die at an early age from a severe lymphoproliferative disorder which suggests a role as a negative regulator of T cell activation (3,418).

1.5.2. C D lla/C D 18 and CD54

CD lla/CD 18 (LFA-1) and its ligand, CD54 (ICAM 1), are adhesion molecules constitutively expressed on both T and B cells (382). Following cross-linking o f the T cell receptor complex, an active form of CD 11 a/CD 18 is induced and CD54 expression is increased (21,124). In response to antigen-specific activation, a CDl la/CD18-CD54-dependent signal is transmitted to the antigen-presenting B cell (237). Interaction between CDl 1 a/CD 18 and CD54 is induced following cross-linking of CD40 and promotes homotypic adhesions and allogeneic T cell proliferation (21). A requirement for CDl la/CD 18-CD54 in T-B cell interactions is highlighted by patients with leukocyte adhesion defect who do not express CD 11 a/CD 18 (303). These patients are able to produce antigen-specific IgG, but antibody titres are low indicating an impairment in the production of memory cells.

1.5.3. CD21 and CD23

CD23 is expressed on a large number of cell types including activated B and T cells, monocytes and follicular dendritic cells (93,109). On B cells, it is an early activation marker induced in response to stimulation by IL-4, IL-13 and CD40 cross-linking (98,100,324). CD23 is the low affinity receptor for IgE (FceRII) and is postulated to

have a role in the regulation of IgE and allergic responses (137,147,183,387). CD23 also binds CD21 and fiinctions as both a signalling molecule and an adhesion molecule (16,39,224,225). CD21-CD23 interactions may promote homotypic and heterotypic interactions following activation (36) and may regulate T-dependent B cell responses, such as IgE production and germinal centre cell survival (38). CD21 is also the receptor for EBV and the iC3b C3dg and C3d fragments of the third component of complement (94). In addition it can form a non-covalent association with CD 19, CD81 and Leu-13 to form a signal transduction complex (395).

1.5.4. CD58 and CD59

CD58 (LFA-3) and CD59 on activated B cells both bind to CD2 on T cells (170,268). Their role in T-dependent B cell activation, although not precisely understood, is indicated by the inhibition of specific antibody responses by blocking mAbs to CD2 or CD58 (126,268).

1.5.5. CD72 and CD5

CD72 is expressed on human pre-B and mature B cells but is absent from plasma cells. Cross-linking with mAbs induces B cell proliferation - either with or without other growth factors and increases both MHC II expression and concentrations of intracellular Ca^^ suggesting that the molecule is a receptor. The ligand for CD72 was reported to be CD5 (although this is not firmly established) (407) which is expressed on all mature T cells and a subset of B cells. mAbs to CD5 can activate T cells and stimulate CD3- and TcR- mediated T cell proliferation, and also stimulate the secretion of IL-2, expression of IL-2R and increase intracellular Ca \ CD5-CD72 interactions may mediate early signals in T-B cell reponses.