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CD 38 and CD 157 as Receptors of the Immune System : A Bridge Between Innate and Adaptive Immunity

INTRODUCTION This manuscript focuses on the evolutionary story of CD38 and CD157 from soluble enzyme of sea mollusks to surface receptors of leukocytes, as described in talks presented at the CD38 meeting (June 10-12, Torino, Italy). We will start by summarizing the presentation by E Ferrero on the evolutionary strategies behind the unique developmental pathway followed by the CD38 gene family. Next, we will analyze some of the immunological aspects of the human CD38 and CD157 molecules, highlighting the common threads emerging from the analysis of different lineages and models, such as T cells (J Sancho), B cells (S Deaglio), dendritic cells (CM Ausiello), and granulocytes (A Funaro). CD38 AND CD157: FROM ENZYMES TO RECEPTORS IN PHYLOGENY Leukocyte receptors would seem to have nothing to do with enzymes, classically portrayed as intracellular nanomachines that churn out new products from one substrate or another. For at least one molecule, this neat division of roles came tumbling down thanks to a single protein sequence alignment (1). At the time, CD38 was a T lymphocyte receptor enjoying a distinguished career as a research tool, diagnostic marker, and therapeutic target in blood cancers. The startling result of this alignment was that the receptor CD38 was related to a NADase/ADPR cyclase (NADase/ADPRC) found in the gonads of Aplysia californica, a sea mollusk. The first step toward solving the enigma of CD38 and CD157 featuring simultaneously as ectoenzymes and receptors starts from the study of molecular evolution as a source of potential explanations of biological phenomena. In this case, the question is by what mechanisms did a cellular enzyme expressed in Aplysia ovotestis find its way to the surface of human leukocytes? NADase/ADPRCs enzymatic activities are found in bacteria (2,3), plants (4), and metazoans (5). The eukaryotic NADase/ ADPRCs form a unique gene family of very small size, which is convenient when trying to catalog new members as orthologs (same gene, different species) or paralogs (genes related by duplication). From sea slug to schistosome, sea urchin, chicken, mouse, macaque, and human, the NADase/ADPRC genes all derive from a common ancestral gene. The oldest well-characterized NADase/ ADPRC gene at the moment belongs to Aplysia, whose origins date back to the Cambrian period over 500 million years ago (mya). The compact 8-exon, 7 kb CD38 and CD157 as Receptors of the Immune System: A Bridge Between Innate and Adaptive Immunity