CD40‐mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent

Abstract

The cytokine lymphotoxin (LT)alpha is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LT alpha expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LT alpha mRNA and surface-expression in human tonsil B cells. Induction of LT alpha mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bis-indolylmaleimide caused negligible inhibition of anti-CD40-induced LT alpha mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')2 fragments strongly inhibits CD40-mediated LT alpha expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LT alpha expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LT alpha mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LT alpha expression. These results suggest that induction of LT alpha expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.

Ectopic lymphoid tissues and local immunity

“…One reason that the development of ectopic lymphoid tissues may not require LTi cells is that these tissues typically form in adults in response to chronic inflammation or infection. Since adults have a wide variety of circulating mature lymphocytes that express LTαβ, particularly when activated [68,69], the role of LTi cells may be performed by activated lymphocytes. In fact, the presence of LTi cells in adults remains a controversial point [70].…”

“…Although B cells are known to be a potent source of surface LTαβ expression [30,68] and are important for maintaining the organization of B cell follicles and FDC networks in conventional lymphoid organs [28,101], B cells are also critical for T cell activation in rheumatoid arthritis [102]. Adoptive transfer experiments using human/mouse chimeras show that activation of CD4 T cells in rheumatoid synovium is strictly dependent on B cells and that non-B cell antigen-presenting cells can not maintain T cell activation on their own [102].…”

CD40 Signaling in B Cells Regulates the Expression of the Pim-1 Kinase Via the NF-κB Pathway

“…These complex cellular responses to CD40 engagement are likely to involve many changes in gene expression. For example, CD40 signaling has been shown to regulate the expression of multiple genes encoding antiapoptotic proteins (Bcl-x L , A1, A20, cIAP2, c-Myc (30 -34)) as well as a variety of genes encoding cell surface proteins that allow B cells to communicate with other cells of the immune system (CD40, CD23, LFA-1, ICAM-1, Fas, B7.1, B7.2 (7,33,(35)(36)(37)(38)(39)). However, it is likely that many other CD40-regulated genes also contribute to the ability of CD40 to promote B cell survival, activation, proliferation, and differentiation.…”

Organizing a mucosal defense

“…ILFs are present in mice lacking T lymphocytes, and therefore T‐lymphocyte responses are not required for ILF formation (30). LT‐sufficient B lymphocytes are required for ILF formation, and accordingly, several stimuli have been identified as inducing the expression of LT in B lymphocytes: major histocompatibility complex class II crosslinking, CD40 ligation, IL‐4R ligation, and chemokine receptor ligation (35–40). The physiological context in which B lymphocytes would receive the majority of these stimuli is during the process of T‐cell help.…”