CD73 Expression Is Dynamically Regulated in the Germinal Center and Bone Marrow Plasma Cells Are Diminished in Its Absence

Abstract

CD73 catalyzes the conversion of extracellular nucleosides to adenosine, modulating inflammatory and T cell responses. Elevated expression of CD73 marks subpopulations of murine memory B cells (MBC), but its role in memory development or function is unknown. Here, we demonstrate that CD73 is progressively upregulated on germinal center (GC) B cells following immunization, is expressed at even higher levels among T follicular helper cells, but is absent among plasma cells (PC) and plasmablasts (PB). We analyzed the T-dependent B cell response in CD73 knockout mice (CD73KO). During the early response, CD73KO and wild type (WT) mice formed GCs, MBCs and splenic PBs and PCs similarly, and MBCs functioned similarly in the early secondary response. Late in the primary response, however, bone marrow (BM) PCs were markedly decreased in CD73KO animals. Tracking this phenotype, we found that CD73 expression was required on BM-derived cells for optimal BM PC responses. However, deletion of CD73 from either B or T lymphocytes alone did not recapitulate the phenotype. This suggests that CD73 expression is sufficient on either cell type, consistent with its function as an ectoenzyme. Together, these findings suggest that CD73-dependent adenosine signaling is prominent in the mature GC and required for establishment of the long-lived PC compartment, thus identifying a novel role for CD73 in humoral immunity.

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

“…It seems likely, then, that IgM memory cells are regulated via adenosine receptors, which likely function by regulating inflammation, as has been reported for CD73. However, our initial studies of CD73-deficient mice have failed to reveal a requirement for this receptor for the generation or function of IgM memory cells (unpublished data), findings which are consistent with other published studies that have reported relatively modest effects of CD73-deficiency in B cells [75]. Nevertheless, further investigation into a role for adenosine and related receptors on memory B cells will likely be informative.…”

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets

“…Consistent with a role for CD73 in CSR, B cells from CVI patients show very low CD73 expression, and CD73 on neonate B cells gradually increases during the first 6 months of life, correlating with their ability to make IgG. In vivo immunization of CD73‐deficient mice, however, revealed only slightly delayed or normal isotype switched responses …”

Blood Stage Malaria Disrupts Humoral Immunity to the Pre-erythrocytic Stage Circumsporozoite Protein

“…Studies with CD80-deficient mice have showed that CD80 plays an important role in regulating interactions between B and T cells during early and late GC formation and lack of CD80 expression leads to an impaired development of long lived plasma cells (Good-Jacobson et al, 2012). Expression of CD73 is also upregulated in highly functional MBCs and its deletion prevented the development of LLPCs in the bone marrow (Conter et al, 2014). To determine whether blood stage infection perturbed the expression of CD80 and CD73, mice were infected with parasites as described above and CSP-specific B cells were analyzed for surface expression of these phenotypic markers 30 days later.…”