Sepsis compromises primary B cell-mediated responses

Abstract

Abstract Sepsis is the leading cause of death in non-coronary ICU’s, and one hallmark of sepsis patients is sustained immune suppression. Septic patients exhibit compromised innate and adaptive immunity, making them highly susceptible to secondary infections. Using the cecal ligation and puncture (CLP) model of sepsis, we recently showed the recovery of CD4 T cells from CLP-induced lymphopenia is accompanied by alterations in the composition and function of the Ag-specific CD4 T cell repertoire. These data led us to hypothesize that CD4 T cell-dependent B cell responses would also be impaired after CLP. Using the same CLP model, we immunized sham (control) and CLP mice with PE-conjugated 2W1S56 peptide 30 d after surgery, and then we quantitated the number of 2W1S-specific CD4 T cells and PE-specific B cells 7 d later. Compared to sham mice, CLP-treated mice immunized with PE-2W1S56 had a sustained reduction in number of 2W1S-specific Tfh CD4 T cells and naïve/memory PE-specific B cells after CLP. Next, we immunized sham and CLP mice with TNP-KLH plus either CpG or alum early (2 d) or late (30 d) after surgery to induce Th1 or Th2 Ab responses, respectively. We observed compromised production of anti-TNP Ab in mice immunized with either TNP-KLH/CpG or alum early (2 d) after CLP. Importantly, Ab production remained reduced in mice immunized with TNP-KLH/alum late (30 d) after CLP. Together, our data show CLP-induced sepsis impacts humoral immunity by affecting the number and function of Ag-specific B cells and CD4 Tfh cells. Moreover, these data suggest potential for defects in humoral immunity to newly introduced Ag (e.g., vaccines) in sepsis survivors long after the septic event has resolved.