Bidirectional regulation of human B cell responses by CD40-CD40 ligand interactions.
Positive and negative effects of CD40 ligation on human B cell function were suggested by the observation that mAb to CD40 ligand partially blocked the suppressive influences of anti-CD3-stimulated control CD4+ T cells, as well as the B cell stimulatory effects of anti-CD3 activated mitomycin C-treated CD4+ T cells. To examine the negative effects of CD40 ligation in greater detail, B cells were cultured with anti-CD3 activated mitomycin C-treated CD4+ T cells that expressed optimal levels of CD40 ligand; additional recombinant human CD40 ligand significantly suppressed Ig production, but not proliferation. In contrast, when B cells were stimulated with SAC (formalinized Cowan I strain Staphylococcus aureus) and IL-2 in the absence of T cells, small amounts of recombinant CD40 ligand-stimulated Ig production, whereas larger quantities directly suppressed Ig secretion. The suppressive action of CD40 ligation on Ig production was most apparent after initial B cell activation. Moreover, IgD-memory B cells were significantly more sensitive to inhibition by CD40 ligation than IgD+ naive B cells. Engagement of CD40 not only suppressed Ig secretion by IgD- memory B cells, but also expression of CD38. Finally, activated B cells acquired the capacity to down-regulate CD40 ligand expression by stimulated CD4+ T cells more effectively than resting B cells. These results indicate that during T cell-B cell collaboration, engagement of CD40 can influence Ig production both positively and negatively, depending on the density of CD40 ligand as well as the stage of B cell activation and differentiation.
Miyashita
T
T
Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75235, USA.
McIlraith
M J
MJ
Grammer
A C
AC
Miura
Y
Y
Attrep
J F
JF
Shimaoka
Y
Y
Lipsky
P E
PE
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000917:Antibody Formation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D006801:Humans; D007108:Immune Tolerance; D007072:Immunoglobulin D / Q000378:metabolism; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008562:Membrane Glycoproteins / Q000502:physiology*; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D007072:Immunoglobulin D; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1