ReviewB lymphocyte activation by contact-mediated interactions with T lymphocytes
Section snippets
Introduction: contact-dependent T cell mediated B cell activation
Although B lymphocytes express receptors that can bind many different soluble biologically active molecules, such as lymphokines and chemokines, the development of affinity maturation and a highly effective humoral memory response require receipt by the B cell of contact-mediated signals from an activated T lymphocyte. This requirement may be advantageous to the regulation of humoral responses in several ways. Although bystander polyclonal activation of B cells by activated T cells occurs, it
MHC class II
It was once widely believed that T cell cytokine production was both necessary and sufficient to mediate full activation of antigen specific B cells. Subsequently, when more stringently separated resting B cells were used, it was shown that, although cytokines clearly play important roles in B cell activation, contact-mediated signals from the T cell are likewise crucial (reviewed in [7]). The first such signal to be identified was MHC class II 8., 9.. Engagement of class II molecules on B
Adhesion molecules
Both B and T lymphocytes express various transmembrane adhesion molecules, whose surface expression is increased after diverse activation signals. Both cell types express ICAM-1 (CD54) and LFA-1 (CD11a–CD18), which bind to each other and can thus mediate both homotypic and heterotypic adhesion. Enhanced adhesiveness between B cells and T cells can amplify activation signals delivered by one cell type to the other; however, the role played by direct signaling through either of these two adhesion
CD72
It has been known for some time that antibody-mediated engagement of the CD72 molecule on B cells stimulates proliferation, enhanced B cell survival and upregulation of MHC class II expression (reviewed in [28]). However, the natural ligand for CD72 had proved elusive. New studies have identified this ligand as CD100, a member of the semaphorin family more commonly known for roles in neuronal regulation, and shown that it is expressed on both B cells and activated T cells [29••]. Engagement of
The TNF and TNF-receptor family
Some of the most biologically important signals that the B cell receives from the cognate activated T cell are delivered through membrane-bound members of the TNF and TNF receptor (TNF-R) family of proteins (see below). The number of identified members of this family is rapidly increasing.
CD40
One of the first TNF family members shown to be of major importance in T cell dependent B cell activation is CD40, a TNF-R family member whose ligand, CD154, is expressed as a membrane-bound trimer on activated T lymphocytes. Engagement of CD40 on B lymphocytes promotes proliferation, antibody secretion, cytokine production, upregulation of various surface molecules involved in antigen presentation, isotype switching, development of germinal centers and a humoral memory response (recently
CD134 ligand and CD137 ligand
Considerable interest has been shown recently in the role played by the TNF-R family molecule OX40/CD134 in T cell co-stimulation. However, earlier studies demonstrated that the CD134 ligand (CD134L), expressed on activated B cells, can itself send signals to B cells that promote proliferation and differentiation 43., 44.. Recent data from CD134L-deficient mice reveal that T cell dependent IgM production is normal but that the production of switched immunoglobulin isotypes is reduced [45••]. In
BCMA and TACI
Two recently identified TNF related proteins, APRIL (‘a proliferation-inducing ligand’ [50]), and TALL-1 [51] (also referred to as BlyS [52] or BAFF [53]), can augment B cell growth and differentiation by signaling through either of the TNF-R family members BCMA or TACI (recently reviewed in [54]). Although potentially important in regulating humoral immune responses, the involvement of APRIL and TALL-1 in T cell contact dependent B cell activation remains to be proved. Myeloid cells seem to be
CD27
CD27 is a TNF-R family member expressed by a subpopulation of B lymphocytes and has been proposed as a marker of memory cells (reviewed in [55]). CD70, a TNF family member and the ligand for CD27, is expressed by T lymphocytes relatively late in their activation [56]. CD27 signals seem to be particularly important in the terminal differentiation of B cells into antibody-secreting plasma cells 57., 58., 59.. Interestingly, CD27 is also expressed by many T lymphocytes, in which one of its roles
CD30 and CD153
In contrast to the generally stimulatory effects of TNF-R family members such as CD27 and CD40, CD30 and its ligand CD153 (a TNF family member) have been proposed as negative regulators of humoral immune responses. Signaling through either molecule on B lymphocytes seems to inhibit isotype switching and may limit both the magnitude of an immune response and activation of low affinity or bystander B cells 63••., 64•.. It should also be noted, however, that B cell homeostasis and humoral immune
CD95
During the activation of a humoral immune response, CD40 signals induce upregulation of CD95/Fas on the responding B lymphocytes, which then become increasingly susceptible to apoptosis induction by CD95L expressed on activated T lymphocytes. Defects in CD95 or its ligand in vivo cause marked dysregulation of humoral immune responses, resulting in hypergammaglobulinemia, splenomegaly, lymphadenopathy and autoimmunity.
Regulation of the immune response by CD95 is the subject of an extensive
Conclusions
It is increasingly evident that a large number of diverse receptor–ligand interactions contribute to the activation of B lymphocytes after contact with the activated T cell. Various types of molecules act as signal receptors for the B cell, including MHC molecules, adhesion molecules, co-stimulators and regulators of the BCR complex, and the rapidly growing TNF-R/TNF superfamily of molecules. For some of these B cell signal receptors, their natural ligands on T cells await identification—a key
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
• of special interest
•• of outstanding interest
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