B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40

Abstract

The expression of CD40 ligand (CD40L) on activated T cells (CD4+ T cell clone MT9) is diminished when the T cells are cultured in the presence of B cells. This effect, observed both with normal tonsil B cells and with the B cell line JY, was detected after 6 h and sustained at least until 18 h of co-culture. Analysis of mRNA showed that CD40L mRNA levels were not modified after 6 h, but were significantly down-regulated after 18 h of co-culture with B cells. Although CD40L expression could not be detected by a CD40-Fc chimera, the molecule was still expressed at the membrane as shown with a polyclonal antiserum against CD40L (anti-TRAP). In addition, T cells activated in the presence of B cells were stained by a polyclonal antiserum against CD40, without the appearance of CD40 mRNA. These results indicated that a soluble form of CD40 (sCD40) bound to the expressed CD40L on T cells. The existence of sCD40 was confirmed by detection of sCD40 in B cell supernatants using a specific enzyme-linked immunosorbent assay. Collectively, these data show that B cells can regulate the expression of CD40L on activated T cells at least by two different mechanisms.

Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients

“…In vitro, sCD40 has been shown to bind to CD40L [47]. This may be interpreted as a mechanism that controls CD40-CD40L interaction in a negative fashion.…”

“…Tumour and CIBD patients showed only weak elevations of sCD40. express high levels of CD40 and have been shown to shed sCD40 in vitro [47].…”

“…This result may be explained by the low serum concentration of sCD40 and does not exclude binding of serum sCD40 in vivo, since CD40Fc was not detected on BHK CD40L when applied at a similar concentration. In view of the finding that sCD40 from cultured B cells bound to CD40L [47], it is not unlikely that sCD40 may act as a negative 156 R. F. Schwabe et al regulator of CD40-CD40L interaction in vivo. A supposed blockade of CD40-CD40L interaction might be held responsible for the decreased inducibility of Th1 cytokines [9] and the defective costimulation via CD28 [10] in uraemic patients [10], since CD40 is a potent up-regulator of IL-12 synthesis [43] and CD28 expression [41].…”

“…Soluble CD40 might exert immunosuppressive effects in a similar fashion by interfering with CD40-CD40L interaction. Soluble CD40 has been demonstrated in vitro in the supernatants of B cell lines and bound to CD40L, which was thought to regulate CD40-CD40L interaction in a negative fashion [47,48]. A dimeric CD40 fusion protein effectively suppressed IL-12 production by monocytes in vitro [49].…”

Modulation of neuronal differentiation by CD40 isoforms

“…CD40 receptor (CD40) is a 45 -50 kDa receptor that is a member of the tumor necrosis factor receptor (TNFR) superfamily 2,3 . CD40 expression and function has been described on a variety of cell types [4][5][6][7] , including neurons 8 . Activation of the CD40 pathway is well-known to promote proliferation, survival, differentiation and maturation in a variety of immune and other cell types [9][10][11][12][13][14][15][16][17][18][19][20] .…”