CD38, an ectoenzyme and a signaling receptor, is a novel marker of human mature monocyte-derived dendritic cells (MDDCs). The working hypothesis is that CD38 is not only a marker but also contributes to functions specifically gained by MDDCs with maturation. This was tested by assessing the role(s) of CD38 after signaling with agonistic anti-CD38 monoclonal antibodies or by blocking the interactions taking place between CD38 and CD31, its counterreceptor. IntroductionCD38 is a pleiotropic cell surface molecule acting as an ectoenzyme and a receptor. The enzymatic activity ends in the synthesis of Ca 2ϩ -mobilizing metabolites (ie, ADP-ribose [ADPR], nicotinic acid adenine dinucleotide phosphate [NAADP], and cyclic ADP-ribose [cADPR]) involved in the regulation of calcium-dependent calcium release. 1,2 CD38 has a unique pattern of surface expression among cells of the human immune system, being present on lymphoid and myeloid progenitors, lost during differentiation, and re-expressed at high density in activated T, B, and natural killer (NK) cells. 3,4 The molecule shows a broad distribution in different tissues. 5 CD38 ligation in immune cells delivers activation signals and induces cytokine production and secretion by T, 6 B, 7 and NK cells 8 and monocytes. 9 CD38 also regulates cell viability by preventing human germinal center B cells from undergoing apoptosis 10 and contributing to increased survival of B-cell chronic lymphocytic leukemia (B-CLL) cells. 11 This panoply of different functional roles may be explained considering some nonconventional features of CD38 as a receptor. The intrinsic ineptitude of CD38 to transduce signals is overcome by working in physical and functional associations with specialized signaling molecules, such as T-cell receptor on T cells, 12-14 B-cell receptor on B cells, 15,16 and CD16 on NK cells. 17 CD38 can sustain adhesion and rolling of CD38 ϩ lymphocytes on endothelial cells through interaction with CD31 (identified as a specific counterreceptor 18 ), suggesting its possible role in lymphocyte trafficking. 19 All the signals mediated by monoclonal antibody (mAb) ligation of CD38 can be reproduced by its interaction with CD31.In murine models, CD38 is involved in chemotaxis and transendothelial migration of both polymorphonuclear leukocytes (PMNs) and dendritic cells (DCs) and this function requires its enzymatic activities. 20,21 Consequently, CD38 knockout mice have impaired capacity to respond to infections. 20 The evaluation of the expression of the molecule also has applications in clinical diagnosis, such as in AIDS (where CD38 is one of the earliest indicators of infection 22 ) and B-CLL (where the expression is generally associated with poor prognosis 15 ). Autoantibodies specific for CD38 are found in diabetes and thyroid disorders. [23][24][25][26] The agonistic properties of these autoantibodies envisage pathogenic role(s) in these diseases.We recently reported a pulsatile pattern of surface CD38 expression in human monocyte-derived dendritic cells (MDDCs). 27 ...

Human CD38 is a surface molecule which has been attributed the function of a signaling channel leading to cellular activation and proliferation, an ectoenzyme with multiple function as well as an inducer of Ca2+ mobilization from cytoplasmic stores. The effect mediated by CD38 have been studied in different cell populations: the results obtained in human B cells are apparently contradictory, with CD38 simultaneously leading to apoptosis in early B cells while increasing survival in cells derived from lymph node germinal center. Other effects recently reported concern a different potential in terms of signaling in early B cells and derived cell lines or in more detailed disease models of human leukemia, namely B chronic lymphocytic leukemia cells. To complete the picture of the effects mediated by CD38 in the B cell compartment, we have studied the signals elicited by ligation of the human molecule in mature B cells from circulating pool and also from spleen of normal individuals. The information obtained completes the picture of CD38 and mature B cells, where we also studied the contribution of relevant cytokines involved in maintenance and differentiation of these normal cells, namely IL-1 alpha, IL-2, IL-4 and IL-6. Our results indicate that human CD38 plays a key role as a co-receptor in mature B cells from normal individuals.

Dendritic cell (DC) maturation is characterized by the gain or loss of immunological functions and by expression of distinctive surface receptors. CD38 is an ectoenzyme that catalyzes the synthesis of cyclic ADP ribose (a potent second messenger for Ca 2+ release), as well as a receptor that initiates transmembrane signaling upon engagement with its counterreceptor CD31 or with agonistic monoclonal antibodies. Since CD38 is expressed by resting monocytes, we aimed to monitor CD38 expression during the differentiation of human monocyte-derived DC (MDDC) and to investigate the possibility that CD38 plays a functional role during DC maturation. CD38 is down-modulated during differentiation into immature MDDC and expressed again upon maturation. The extent of CD38 expression is dependent on the stimulus adopted (LPS G IFN-+ G CD40 cross-linking). Although weak, IFN-+ consistently induces DC maturation. De novo-synthesized CD38 is enzymatically active, and its expression in mature (m) MDDC is dependent on NF-‹ B activity. However, CD38 is not merely a maturation marker but also mediates signaling in mMDDC, where it maintains its functions as a receptor. Activation via agonistic anti-CD38 mAb induces up-regulation of CD83 expression and IL-12 secretion, whereas disruption of CD38/CD31 interaction inhibits CD83 expression, IL-12 secretion and MDDC-induced allogeneic T cell proliferation.

Cytokine profiles were examined 1 month after primary vaccination of infants with a whole-cell pertussis vaccine (wP) (Connaught) or either of two acellular pertussis vaccines, aP-Chiron Biocine (aP-CB) or aP-SmithKline Beecham (aP-SB), each combined with diphtheria-tetanus toxoids (DT), in Bordetella pertussis antigen-stimulated or unstimulated peripheral blood mononuclear cells (PBMC). Pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) were used as antigens, and the children were defined as responsive when their PBMC proliferated in response to these antigens. The controls were either children who received only DT or children who received pertussis vaccine but whose PBMC did not proliferate upon stimulation with B. pertussis antigens (unresponsive children). Antigen-stimulated PBMC of responsive wP recipients were characterized by an elevated production of T-helper-cell type 1 cytokines gamma interferon (IFN-␥) and interleukin 2 (IL-2), low to minimal production of IL-5, and no production of IL-4. The PBMC of aP vaccine-responsive recipients showed, in addition to the elevated IFN-␥ production, a consistent, antigendependent production of type 2 cytokines (IL-4 and IL-5), with PRN being the most and PT being the least effective antigen. Type 2 cytokine induction was more pronounced in aP-SB than in aP-CB recipients, as shown by the presence of IL-4 mRNA transcripts and higher IL-5 production in the former (161.6 ؎ 36 and 47.9 ؎ 44 pg/ml [mean ؎ standard error for five subjects each], respectively, after PRN stimulation). Appreciable, antigen-unstimulated (constitutive) IFN-␥ production was also detected in PBMC cultures of all vaccinees. However, this spontaneous IFN-␥ production was, in most vaccinees, significantly lower than the antigendriven cytokine production. In contrast, no constitutive type 2 cytokine production was ever observed in any vaccine group. PBMC from the two control groups (either DT or pertussis vaccine recipients) did not show any type 2 cytokine production, while IFN-␥ production was comparable in both antigen-stimulated and unstimulated conditions. Absence of type 2 cytokines and low levels of constitutive IFN-␥ production were also seen in prevaccination children. Thus, pertussis vaccines induce in infants a basically type 1 cytokine profile, which is, however, accompanied by some production of type 2 cytokines. The latter are more expressed by aP-SB than by aP-CB recipients, and with PRN than with other antigens, and they are minimally expressed in wP recipients and with PT as antigen. Our data also highlight a constitutive IFN-␥ production in infancy, which might reflect natural immunization and/or the burden of concomitant vaccinations and which may have an impact on T-helper-cell cytokine pattern polarization consequent to pertussis vaccination.