Marginating transitional B cells modulate neutrophils in the lung during inflammation and pneumonia

Abstract

Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation dominated by transitional type 1 B and type 2 B (T2B) cells. Lung intravital confocal microscopy revealed that T2B cells marginate in the pulmonary capillaries via CD49e and require CXCL13 and CXCR5. During lung inflammation, marginated T2B cells dampened excessive neutrophil vascular inflammation via the specialized proresolving molecule lipoxin A4 (LXA4). Exogenous CXCL13 dampened excessive neutrophilic inflammation by increasing marginated B cells, and LXA4 recapitulated neutrophil regulation in B cell–deficient mice during inflammation and fungal pneumonia. Thus, the lung microvasculature is enriched in multiple IgM+ B cell subsets with marginating capillary T2B cells that dampen neutrophil responses.

T2B or not to B: Calming neutrophils offshore

“…In this context, the neutrophils regulate the proliferation and maturation of marginal zone B cells ( Puga et al, 2011 ). There are additional B cells in the single-cell RNA sequencing from this study that await further characterization ( Podstawka et al, 2021 ), and parallels with the spleen suggest that studies of the pulmonary microvascular niche may also teach us about the spleen and other secondary lymphoid organs. These new data also suggest that the vasculature may be an additional level of regulation for circulating immune cells outside of conventional lymphoid tissues.…”

“…This naive B cell population originates from the bone marrow and accumulates in the spleen, where they develop into mature B cells that subsequently recirculate. Podstawka et al (2021) observed that the T2B cells respond to CXCL13 expressed by the lung tissue and marginate, remaining endothelial bound within capillaries for up to 10 min, in a similar manner to neutrophils. The prolonged positioning of the T2B cells with neutrophils within the lung microvasculature provides a unique opportunity for these cell types to interact, and the authors show that B cell margination serves to limit intravascular neutrophil clustering and promote their apoptosis in a lipoxin A4 (LXA4)–dependent manner in response to inflammatory insults.…”

“…Yipp and colleagues have previously shown that B cells can promote marginating, aged neutrophils to undergo apoptosis. In this issue of JEM , the same group expands upon this work by showing that a specific subset of B cells preferentially marginate and can prevent neutrophil clustering in the lung microvasculature ( Podstawka et al, 2021 ).…”

“…Using an elegant combination of intravital microscopy and single-cell RNA sequencing, Podstawka et al (2021) show that B cells marginate within the pulmonary microvasculature even during homeostasis and identify these B cells as transitional type 2 B (T2B) cells. This naive B cell population originates from the bone marrow and accumulates in the spleen, where they develop into mature B cells that subsequently recirculate.…”

“…Serum CXCL13 has been examined as a biomarker of disease in a number of conditions. The study of Podstawka et al (2021) has the potential to lead to functional understanding of circulating CXCL13 and ensuing therapeutic targeting.…”