CD154 Restricts Helminth-Induced Macrophage Polarisation and Proliferation While Promoting Tissue Residence

Abstract

CD154 (CD40L) is of central importance in effector responses mediated by classically activated macrophages. However, there is limited information on the impact of CD154 on macrophage responses in type 2 contexts, characterised by IL-4-induced polarisation and proliferation. CD154 restricts the polarisation and proliferation of peritoneal cavity macrophages in response to exogenous IL-4. Here we address the impact of CD154 on peritoneal macrophages during infection of mice with the intestinal helminth Heligmosomoides polygyrus. This strictly enteric nematode causes recruitment of Th2 cells and macrophages to the peritoneal cavity alongside type 2 polarisation and proliferation of recruited and resident macrophages. Nine days post-infection, there was an increase in the expression of cell-surface CD154 in CD4+ T cells together with increased IL-13 levels in the cavity, suggestive of local antigen presentation. Blocking CD154 enhanced the proliferation of resident but not of recently recruited macrophages. CD154 blocking additionally potentiated the expression of type 2 marker Ym1 (Chil3) in resident and recruited macrophages. Unexpectedly, CD154 blocking caused increases in the numbers of recently recruited macrophages and the appearance of cells with characteristics of both differentiating recruited macrophages (expression of folate receptor β and MHCII) and resident macrophages (high-level expression of F4/80 and CD102). Together, these observations suggest that CD154 promotes the acquisition of tissue residence by recruited macrophages. Thus, our results indicate that in a helminth infection CD154 restricts certain aspects of the polarisation and proliferation of macrophages in response to type 2 cytokines while promoting the acquisition of resident phenotype by the recruited macrophages.