Signaling properties of CD38 in the mouse immune system: enzyme-dependent and -independent roles in immunity

Abstract

The 5th international CD38 meeting, held in Torino, Italy, spanned a range of topics from the role of CD38 as a signaling receptor in lymphocytic tumors to the importance of CD38-derived metabolites in NAD(+) metabolism, calcium signaling, and immune function. This meeting was particularly exciting as data were presented demonstrating that collaborative experiments between enzymologists, biochemists, cell biologists, immunologists, and clinicians have started to unravel the secrets of CD38 biology. It is now clear that all of the products of the CD38 enzyme reaction regulate calcium signal transduction in cell types as diverse as sea urchin oocytes and mammalian lymphocytes. It is also apparent that CD38 plays important immunomodulatory role(s), however there is still much debate on how CD38 mediates its immunoregulatory functions and whether the enzymatic products generated by CD38 are important for immunity. The data presented at this meeting have begun to resolve some of these controversies. First, CD38 regulates the function of leukocytes by enzyme-dependent and enzyme-independent mechanisms. Second, CD38 regulates inflammatory responses by modulating the activity of the responding leukocytes and by altering the activity of non-hematopoietic cells in the inflamed tissue. Finally, crosstalk between CD38 and other NAD(+) utilizing enzymes such as ART2, SIRT1, and PARP-1 impacts NAD(+) homeostasis, inflammation, and immunity. Thus, immunity is regulated by CD38 in multiple and unexpected ways and the new research challenge will be to determine whether we can exploit the complex biology of CD38 to therapeutically regulate the immune system.

Figure 1

Multi-faceted roles for CD38 in immune responses and inflammation. Although CD38 was first described as a lymphocyte-restricted plasma membrane signaling receptor, it is now apparent that CD38 plays a diverse set of roles not only on lymphocytes but also on dendritic cells (DCs), granulocytes and multiple non-bone marrow derived cells, including airway smooth muscle cells (ASM) and pancreatic β-cells. In some cells types like ASM cells and DCs, CD38 regulates signaling by catalyzing the production of the calcium-mobilizing second messengers cADPR, NAADP ⁺ and ADPR. However, in other cells types, like β-cells and T cells, CD38 may indirectly regulate signaling by catabolizing NAD⁺ and altering or preventing the activity of NAD ⁺ –metabolizing enzymes such as ART2, SIRT1, and PARP. Finally, in some cell types, including B lymphocytes, CD38 appears to regulate cell signaling by enzyme-independent mechanisms. Thus, while it is clear that CD38 modulates immune responses, the process is complex and involves multiple CD38-expressing cell types and several different calcium-dependent and calcium-independent signaling pathways. Our new challenge will be to understand how all of these individual CD38-dependent signaling pathways interact with one another to regulate the global immune response to pathogens, allergens and autoantigens.