Universal expression and dual function of the atypical chemokine receptor D6 on innate-like B cells in mice

Abstract

Mouse innate-like B cells are a heterogeneous collection of multifunctional cells that control infection, play housekeeping roles, contribute to adaptive immunity, and suppress inflammation. We show that, among leukocytes, chemokine internalization by the D6 receptor is a unique and universal feature of all known innate-like B-cell populations and, to our knowledge, the most effective unifying marker of these cells. Moreover, we identify novel D6 active B1-cell subsets, including those we term B1d, which lack CD5 and CD11b but exhibit typical B1-cell properties, including spontaneous ex vivo production of IgM, IL-10, and anti-phosphorylcholine antibody. The unprecedented opportunity to examine D6 on primary cells has allowed us to clarify its ligand specificity and show that, consistent with a scavenging role, D6 internalizes chemokines but cannot induce Ca 2؉ fluxes or chemotaxis. Unexpectedly, however, D6 can also suppress the function of CXCR5, a critical chemokine receptor in innate-like B-cell biology. This is associated with a reduction in B1 cells and circulating classswitched anti-phosphorylcholine antibody in D6-deficient mice. Therefore, in the present study, we identify a unifying marker of innate-like B cells, describe novel B1-cell subsets, reveal a dual role for D6, and provide the first evidence of defects in resting D6-deficient mice.

Regulatory functions of innate-like B cells

“…However, the developmental pathways of human ILBs are largely unknown, and the study of IL-10 producing human Bregs is just in its infancy. Recently, the atypical chemokine receptor D6 83 and T-cell Ig domain and mucin domain protein 1 84 were used to identify murine ILBs and IL-10-producing Bregs, respectively. Whether there are any similar markers that could characterize corresponding human B-cell subsets is an interesting question to be addressed in the future.…”

Expression of plasma cell alloantigen 1 defines layered development of B-1a B-cell subsets with distinct innate-like functions

“…Recently, Rothstein and coworkers identified PD-L2 + (57) and CD25 + B-1a subsets (58). By using a decoy receptor for many CC chemokines, D6, as a marker, Hansell et al described the division of B-1a cells into four subpopulations (59). None of these subsets, however, has been well characterized in terms of their developmental origins, molecular features, and cellular functions.…”

The Chemokine Decoy Receptor D6 Prevents Excessive Inflammation and Adverse Ventricular Remodeling After Myocardial Infarction

“…We propose a model where ischemia induces CC-chemokines in the ischemic heart, leading to the recruitment of pathogenic inflammatory Ly6Chi monocytes and neutrophils, and where D6 acts as a gatekeeper of uncontrolled inflammation through the regulation of CC-chemokine levels. D6 is known to be expressed by lymphatic endothelial cells 10 and some specific leukocyte population such as innatelike B cells 16 and transforming growth factor-β-activated macrophages. 17 Our data clearly suggest that D6 is preferentially expressed in the infarcted heart, as it was undetectable in viable human myocardium and its mRNA expression strongly raised after MI in mice.…”