Experimental Sepsis Impairs Humoral Memory in Mice

Pötschke, Christian; Keßler, Wolfram; Maier, Stefan A.; Heidecke, Claus–Dieter; Bröker, Barbara M.

doi:10.1371/journal.pone.0081752

Cited by 16 publications

(20 citation statements)

References 64 publications

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“…More recently, post-mortem assessment of T cells from patients who died from severe sepsis showed almost no production of IFNγ, TNFα, IL-6, and IL-10 after anti-CD3/CD28 mAb stimulation compared to samples from non-septic, control patients ( 36 )—further supporting the idea that sepsis affects general T cell function. Indirect evidence of defective CD4 T cell function has come from other studies describing altered humoral responses after sepsis, specifically in terms of Ag-specific immunity (e.g., T cell-dependent Ab responses) ( 37 , 38 ). With this clinical information in mind, we wanted to further investigate how sepsis affects the generation of a primary CD4 T cell-dependent B cell response using the CLP mouse model of polymicrobial sepsis.…”

Section: Resultsmentioning

confidence: 99%

Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses

et al. 2018

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Immunosuppression is one hallmark of sepsis, decreasing the host response to the primary septic pathogens and/or secondary nosocomial infections. CD4 T cells and B cells are among the array of immune cells that experience reductions in number and function during sepsis. “Help” from follicular helper (Tfh) CD4 T cells to B cells is needed for productive and protective humoral immunity, but there is a paucity of data defining the effect of sepsis on a primary CD4 T cell-dependent B cell response. Using the cecal ligation and puncture (CLP) mouse model of sepsis induction, we observed reduced antibody production in mice challenged with influenza A virus or TNP-KLH in alum early (2 days) and late (30 days) after CLP surgery compared to mice subjected to sham surgery. To better understand how these CD4 T cell-dependent B cell responses were altered by a septic event, we immunized mice with a Complete Freund's Adjuvant emulsion containing the MHC II-restricted peptide 2W1S56−68 coupled to the fluorochrome phycoerythrin (PE). Immunization with 2W1S-PE/CFA results in T cell-dependent B cell activation, giving us the ability to track defined populations of antigen-specific CD4 T cells and B cells responding to the same immunogen in the same mouse. Compared to sham mice, differentiation and class switching in PE-specific B cells were blunted in mice subjected to CLP surgery. Similarly, mice subjected to CLP had reduced expansion of 2W1S-specific T cells and Tfh differentiation after immunization. Our data suggest CLP-induced sepsis impacts humoral immunity by affecting the number and function of both antigen-specific B cells and CD4 Tfh cells, further defining the period of chronic immunoparalysis after sepsis induction.

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Section: Resultsmentioning

confidence: 99%

Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses

et al. 2018

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“…In models of autoimmunity, sepsis, or chronic inflammation, aberrant expansion of short-lived ASCs has been shown to disrupt the establishment and retention of a LLPC population (53–58). We found that accumulation of BM ASCs was defective in mice challenged with Δ srrAB 14 days earlier (Supplemental Figure 3E), and by 14 days post-challenge, no bacteria were found in the kidneys of mice from any group (data not shown) .…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells

Keener

Thurlow

Kang

et al. 2017

The Journal of Immunology

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Infection with Staphylococcus aureus does not induce long-lived protective immunity for reasons that are not completely understood. Human and murine vaccine studies support a role for antibodies in protecting against recurring infections, but S. aureus modulates the B cell response through expression of Staphylococcal Protein A (SpA), a surface protein that drives polyclonal B cell expansion and induces cell death in the absence of co-stimulation. In this murine study, we show that SpA altered the fate of plasmablasts and plasma cells (PCs) by enhancing the short-lived extrafollicular response and reducing the pool of bone marrow (BM)-resident long-lived PCs (LLPCs). The absence of LLPCs was associated with a rapid decline in antigen-specific, class-switched antibody. In contrast, when previously inoculated mice were challenged with isogenic Δspa S. aureus, cells proliferated in the BM survival niches and sustained long-term antibody titers. The effects of SpA on PC fate were limited to the secondary response, as antibody levels and the formation of B cell memory occurred normally during the primary response in mice inoculated with either WT or Δspa S. aureus. Thus, failure to establish long-term protective antibody titers against S. aureus was not a consequence of diminished formation of B cell memory; instead, SpA reduced the proliferative capacity of PCs that entered the BM, diminishing the number of cells in the long-lived pool.

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“…Interestingly, several investigators have also observed alterations in humoral responses after sepsis, specifically in terms of antigen-specific immunity (e.g. T cell-dependent antibody responses) [97][98][99].…”

Section: Altered Effector Cd4 T Cell Phenotype And/or Functionmentioning

confidence: 99%

Impact of sepsis on CD4 T cell immunity

Cabrera-Pérez¹,

Condotta

Badovinac

et al. 2014

Journal of Leukocyte Biology

154

124

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Sepsis remains the primary cause of death from infection in hospital patients, despite improvements in antibiotics and intensive-care practices. Patients who survive severe sepsis can display suppressed immune function, often manifested as an increased susceptibility to (and mortality from) nosocomial infections. Not only is there a significant reduction in the number of various immune cell populations during sepsis, but there is also decreased function in the remaining lymphocytes. Within the immune system, CD4 T cells are important players in the proper development of numerous cellular and humoral immune responses. Despite sufficient clinical evidence of CD4 T cell loss in septic patients of all ages, the impact of sepsis on CD4 T cell responses is not well understood. Recent findings suggest that CD4 T cell impairment is a multipronged problem that results from initial sepsis-induced cell loss. However, the subsequent lymphopenia-induced numerical recovery of the CD4 T cell compartment leads to intrinsic alterations in phenotype and effector function, reduced repertoire diversity, changes in the composition of naive antigen-specific CD4 T cell pools, and changes in the representation of different CD4 T cell subpopulations (e.g., increases in Treg frequency). This review focuses on sepsis-induced alterations within the CD4 T cell compartment that influence the ability of the immune system to control secondary heterologous infections. The understanding of how sepsis affects CD4 T cells through their numerical loss and recovery, as well as function, is important in the development of future treatments designed to restore CD4 T cells to their presepsis state.

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Experimental Sepsis Impairs Humoral Memory in Mice

Cited by 16 publications

References 64 publications

Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses

Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses

Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells

Impact of sepsis on CD4 T cell immunity

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