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

Abstract

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.

• Authors: Frances V Sjaastad, Stephanie A Condotta, Jessica A Kotov, Kathryn A Pape, Cody Dail, Derek B Danahy, Tamara A Kucaba, Lorraine T Tygrett, Katherine A Murphy, Javier Cabrera-Perez, Thomas J Waldschmidt, Vladimir P Badovinac, Thomas S Griffith
• Journal: Frontiers in immunology (Front Immunol) Vol. 9 Pg. 2532 ( 2018) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 30429857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies
• Antigens, Bacterial
• Cytokines

Topics

• Animals
• Antibodies (metabolism)
• Antigens, Bacterial (immunology)
• B-Lymphocytes (immunology)
• Cecum (surgery)
• Cell Differentiation
• Cells, Cultured
• Chronic Disease
• Coinfection (immunology)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Immune Tolerance
• Influenza A virus (physiology)
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Orthomyxoviridae Infections (immunology)
• Sepsis (immunology)
• T-Lymphocytes, Helper-Inducer (immunology)