Natural antibodies sustain differentiation and maturation of human dendritic cells

Jagadeesh Bayry ^*, Sébastien Lacroix-Desmazes ^*, Vladimira Donkova-Petrini ^*, Cédric Carbonneil ^*, Namita Misra ^*, Yves Lepelletier , Sandrine Delignat ^*, Sooryanarayana Varambally ^*, , Eric Oksenhendler , Yves Lévy ^¶, Marianne Debré ^||, Michel D. Kazatchkine ^*, Olivier Hermine , and Srini V. Kaveri ^*, **

^*Institut National de la Santé et de la Recherche Médicale Unité 430 and Université Pierre et Marie Curie, Institut des Cordeliers, 75006 Paris, France; Department of Hematology and Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8603, Hôpital Necker-Enfants-Malades, 75015 Paris, France; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Clinical Immunopathology, Hôpital Saint Louis, 75010 Paris, France; ^¶Service d'Immunologie Clinique, Hôpital Henri Mondor, 94010 Créteil Cedex, France; and ^||Institut National de la Santé et de la Recherche Médicale Unité 429, Hôpital Necker-Enfants-Malades, 75015 Paris, France

Received for publication March 29, 2004.

Abstract: The differentiation and maturation of dendritic cells (DCs) is governed by various signals in the microenvironment. Monocytes and DCs circulate in peripheral blood, which contains high levels of natural antibodies (NAbs). NAbs are germ-line-encoded and occur in the absence of deliberate immunization or microbial aggression. To assess the importance of NAbs in the milieu on DC development, we examined the status of DCs in patients with X-linked agammaglobulinemia, a disease characterized by paucity of B cells and circulating antibodies. We demonstrate that the in vitro differentiation of DCs is severely impaired in these patients, at least in part because of low levels of circulating NAbs. We identified NAbs reactive with the CD40 molecule as an important component that participates in the development of DCs. CD40-reactive NAbs restored normal phenotypes of DCs in patients. The maturation process induced by CD40-reactive NAbs was accompanied by an increased IL-10 and decreased IL-12 production. The transcription factor analysis revealed distinct signaling pathways operated by CD40-reactive NAbs compared to those by CD40 ligand. These results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.

Abbreviations: DC, dendritic cell; APC, antigen-presenting cell; NAb, natural Ab; XLA, X-linked agammaglobulinemia; btk, Bruton's tyrosine kinase; IVIg, intravenous Ig; mo-DC, monocyte-derived DC; GM-CSF, granulocyte/macrophage colony-stimulating factor; CD40L, CD40 ligand; MLR, mixed lymphocyte reaction; MFI, mean fluorescence intensity; Th1, T helper 1.

^** To whom correspondence should be addressed at: Institut National de la Santé et de la Recherche Médicale Unité 430, Institut des Cordeliers, 15 Rue de l'Ecole de Médecine, 75006 Paris, France. E-mail: srini.kaveri{at}u430.bhdc.jussieu.fr.

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