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Does CD40 Ligation Induce B Cell Negative Selection?¹

Jesús Martínez-Barnetche^*, Vicente Madrid-Marina, Richard A. Flavell and José Moreno^*,2

^* Research Unit on Autoimmune Diseases, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, Distrito Federal, México; Department of Molecular Virology, Center for Research in Infectious Diseases, Instituto Nacional de Salud Pública, Cuernavaca, México; Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520

Binding of CD154 to its receptor, CD40, provides costimulation for mature B cell activation and differentiation in response to Ag receptor signals. In mice, early B cell precursors express CD40, but its function at this stage is unknown. We examined the effects of CD40 ligation during B cell ontogeny in transgenic mice constitutively expressing CD154 on B cells (EP-CD154). Precursors beyond pro-B cells were absent in adult bone marrow but were increased in the fetal liver. Newborn EP-CD154 mice had largely increased numbers of peripheral B cells, which were CD154⁺, and that 36 h after birth expressed high surface levels of CD23 and MHC class II, resembling activated mature B cells. Nevertheless, EP-CD154 mice were hypogammaglobulinemic, indicating that the expanded population of apparently activated B cells was nonfunctional. Further analysis revealed that soon after birth, EP-CD154 mice-derived B cells became CD5⁺/Fas⁺, after which progressively decreased in the periphery in a CD154-CD40-dependent manner. These results indicate that CD40 ligation during B cell ontogeny induces negative selection characterized by either hyporesponsiveness or an arrest in maturation depending on the time of analysis and the anatomic site studied.