Potential immaturity of the T-cell and antigen-presenting cell interaction in cord blood with particular emphasis on the CD40-CD40 ligand costimulatory pathway

Abstract

There are reports of immaturity of the neonatal immune system, which may explain the low incidence of graft-versus-host-disease (GVHD) after cord blood transplantation. The CD40 ligand (CD40L)-CD40 interaction is important in regulating the cellular immune response. We hypothesized that the neonatal immune system may show immaturity in this interaction. We studied the function of the CD40L-CD40 interaction in the T-cell interaction with B cells and monocytes in cord blood compared with adult blood in vitro. Consistent with previous reports, CD4+ T cells do not express CD40L after T-cell activation. In whole blood, adult monocytes, but not neonatal monocytes, were activated following T-cell activation. However, the activation of adult monocytes was not dependent on the CD40L-CD40 interaction. Using the CD40L trimer (Lt), we showed that cord B cells have comparable responses to CD40 ligation to those of the adult B cells. Both cord and adult monocytes do not respond as well as B cells and this is probably related to low density of expression of CD40. However, interferon-gamma up-regulated CD40 on adult monocytes but not on cord monocytes. This potentiated the adult monocyte response to CD40 ligation by CD40Lt. Our findings suggest that the neonatal CD40L-CD40 pair is immature in the cellular immune response involving monocytes and that interferon-gamma fails to activate neonatal monocytes for a response to CD40L. These findings suggest that in the inflammatory microenvironment of cord blood transplantation neonatal monocytes may play a minor role in the effector arm of the immune response. This finding may be one of several mechanisms for the low incidence of GVHD that is observed following cord blood transplantation. Also the ligand-receptor immaturity may contribute to the increased susceptibility of newborns to certain infections.

Figure 1

Comparison of the up-regulation of B7 costimulatory molecules and adhesion molecules CD11a and CD58 on adult and neonatal B cells following stimulation of T cells by PHA (10 μg/ml) and αCD28 (10 μg/ml) in whole blood. Both adult and cord B cells responded similarly. CD25 was used as a marker of B-cell activation. Adult B cells compared to neonatal B cells responded differently with respect to CD86 and CD11a; P = 0·0031 and P = 0·002, respectively.

Figure 2

The incidence of expression of B7 costimulatory molecules and adhesion molecules CD11a and CD58 on adult B cells following T-cell activation in whole blood. Addition of αCD40L inhibited the up-regulation of these molecules on B cells.

Figure 3

Comparison of the up-regulation of B7 costimulatory molecules and adhesion molecules CD11a and CD58 on adult and neonatal monocytes following T-cell activation in whole blood. Cord monocytes were not activated in whole blood following T-cell activation whereas adult monocytes were (CD25 up-regulation, P = 0·0001). Adult monocytes up-regulated CD80 significantly compared with cord monocytes, P = 0·0001.

Figure 4

Comparison of the up-regulation of B7 costimulatory molecules and adhesion molecules on adult and cord B cells following stimulation by CD40Lt (1·0 µg/ml). Both adult and cord B cells responded similarly. CD25 used as a marker of B cell activation. The response of adult and neonatal B cells was not significantly different.

Figure 5

Comparison of the up-regulation of B7 costimulatory molecules and adhesion molecules on adult and cord monocytes following stimulation by CD40Lt (1·0 μg/ml). Both adult and cord monocytes responded poorly. CD25, used as a marker of monocyte activation, showed significant activation of adult monocytes, P = 0·0001. CD80 was up regulated on adult monocytes (P = 0·05) but CD86 was up-regulated on neonatal monocytes, P = 0·0072.