Marginal zone SIGN-R1 ⁺ macrophages are essential for the maturation of germinal center B cells in the spleen

Abstract

The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+macrophages, DCIR2+dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+macrophages to the spleen corrected positioning of DCIR2+DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.

Prostaglandin E2induction by cytosolicListeria monocytogenesin phagocytes is necessary for optimal T-cell priming

“…For this reason, we hypothesized that subsets such as these may still be producing sufficient levels of PGE2 to drive T-cell responses. One way to assess the role of MARCO + MZMs is use of a new cre recombinase-driving promoter, SIGN-R1, developed by Pirgova et al [27]. SIGN-R1 is a lectin binding receptor expressed on MZMs and drives more efficient deletion of genes by the cre/lox system [27].…”

“…One way to assess the role of MARCO + MZMs is use of a new cre recombinase-driving promoter, SIGN-R1, developed by Pirgova et al [27]. SIGN-R1 is a lectin binding receptor expressed on MZMs and drives more efficient deletion of genes by the cre/lox system [27]. Generation of triple COX-2 knockout mice that express the SIGN-R1-cre in combination with our reported Lyz2-cre CD11c-cre model could be informative about the role of MZMs in production of PGE2.…”

“…However, deletion of COX-2 in Lyz2 + and CD11c + cells did not completely abrogate PGE2 production in vivo. These data led us to hypothesize that other phagocytic cell subsets not effectively targeted by these cre-drivers may be producing the residual PGE2, such as marginal zone macrophages (MZMs), metallophilic macrophages, or other CD11b + cells more broadly [26,27]. To test this hypothesis, we utilized short-term clodronate liposomes to rapidly deplete phagocyte populations in the spleen.…”

Prenatal Development and Function of Human Mononuclear Phagocytes

“…Formation of white pulp and the germinal center occurs in the presence of CD209 in humans and SIGN-R1 + in murine marginal zone macrophages (MZM) (Steiniger et al, 2007;Endo et al, 2015;Pirgova et al, 2020). After birth, MZM and marginal metallophilic macrophage generation are dependent upon the nuclear liver X receptor (LXR) and function to filter the blood as it is released into the marginal zone (A- Gonzalez et al, 2013).…”

“…Splenic pre-follicular DCs secreting CXCL13 and driving B-cell chemotaxis also contribute to white pulp and marginal zone development after birth (Pirgova et al, 2020). Human fetal spleen cDC1s and cDC2s, observed by 13 PCW, have been observed to induce differentiation of T-regulatory (Treg) cells in vitro from adult T-cells.…”