Alteration in TNFα mediates impaired antigen-specific humoral responses in sepsis survivors

Abstract

Abstract Sepsis survivors show impaired responsiveness to antigen (Ag), which is linked to increased susceptibility to infection. Using the cecal ligation and puncture (CLP) model of sepsis, we showed that CLP surviving mice have a reduced antibody response to the T-dependent Ag, NP-CGG, compared to mice that underwent a sham procedure, but an intact response to the T-independent Ag, NP-Ficoll. CLP mice have reduced TNFα levels due to sustained vagus nerve activity. We hypothesized that reduced TNFα production might lead to disruption in follicular dendritic cell (FDC) function and impaired germinal center (GC) responses. FDCs play a key role in GC responses and TNFα is critical for FDC clustering and maturation. Immunofluorescence staining in spleens showed a reduced number of FDC clusters and reduced binding of immune complexes on FDCs in CLP mice compared to sham mice. NP-specific GC B cells sorted from CLP mice immunized with NP-CGG exhibit reduced TNFα, AICDA, and BCL6 mRNA expression compared to sham mice. To confirm the role of the vagus nerve in impaired FDC clusters, CLP mice were subjected to bilateral subdiaphragmatic vagotomy 2 weeks post-CLP. These mice exhibit increased anti-NP IgG levels in response to immunization with NP-CGG compared to non-vagotomized CLP mice. FDC are radioresistant cells; therefore, we lethally irradiated sham and CLP mice and reconstituted them with bone marrow cells from naive mice that never experienced sepsis. CLP mice still show an impaired Ag-specific response confirming involvement of FDCs and vagus nerve signals. In summary, our data suggest that altered vagus nerve activity, low TNFα, and disruption in FDC function contributes to reduced Ag-specific humoral responses in sepsis survivors.