Polymicrobial Sepsis Impairs Antigen-Specific Memory CD4 T Cell-Mediated Immunity

Abstract

Patients who survive sepsis display prolonged immune dysfunction and heightened risk of secondary infection. CD4 T cells support a variety of cells required for protective immunity, and perturbations to the CD4 T cell compartment can decrease overall immune system fitness. Using the cecal ligation and puncture (CLP) mouse model of sepsis, we investigated the impact of sepsis on endogenous Ag-specific memory CD4 T cells generated in C57BL/6 (B6) mice infected with attenuated Listeria monocytogenes (Lm) expressing the I-A b -restricted 2W1S epitope (Lm-2W). The number of 2W1S-specific memory CD4 T cells was significantly reduced on day 2 after sepsis induction, but recovered by day 14. In contrast to the transient numerical change, the 2W1S-specific memory CD4 T cells displayed prolonged functional impairment after sepsis, evidenced by a reduced recall response (proliferation and effector cytokine production) after restimulation with cognate Ag. To define the extent to which the observed functional impairments in the memory CD4 T cells impacts protection to secondary infection, B6 mice were infected with attenuated Salmonella enterica- 2W ( Se -2W) 30 days before sham or CLP surgery, and then challenged with virulent Se- 2W after surgery. Pathogen burden was significantly higher in the CLP-treated mice compared to shams. Similar reductions in functional capacity and protection were noted for the endogenous OVA 323 -specific memory CD4 T cell population in sepsis survivors upon Lm-OVA challenge. Our data collectively show CLP-induced sepsis alters the number and function of Ag-specific memory CD4 T cells, which contributes (in part) to the characteristic long-lasting immunoparalysis seen after sepsis.

Follicular dendritic cell dysfunction contributes to impaired antigen-specific humoral responses in sepsis-surviving mice

“…It is well-documented that sepsis leads to impaired adaptive immune responses, including reduced Ag-specific humoral responses (20)(21)(22). B and T cell defects have been demonstrated in sepsis mice (21)(22)(23), but there are some less well-examined cell types, including FDCs, the dysfunction of which may also contribute to the overall defect. Some reports show that FDCs undergo apoptosis at the onset of sepsis through a caspase-3-mediated mechanism (24,25).…”

Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells

“…These profound impairments are sufficient to reduce the 5 year survival of septic cohorts, relative to non-septic cohorts; consequently, the majority of sepsis-associated mortality is late mortality secondary to the cytokine storm ( Dombrovskiy et al, 2007 ; Donnelly et al, 2015 ; Gaieski et al, 2013 ). This immunologic impairment is typified by transient lymphopenia and reduced capacity of various surviving lymphocyte populations to perform effector function ( Hotchkiss et al, 2016 ; Hotchkiss et al, 2013 ), including CD4 ( Cabrera-Perez et al, 2014 ; Cabrera-Perez et al, 2015 ; Chen et al, 2017 ; Jensen et al, 2020 ; Martin et al, 2020 ; Sjaastad et al, 2020b ) and CD8 T cells ( Condotta et al, 2013 ; Danahy et al, 2017 ; Danahy et al, 2019 ; Duong et al, 2014 ; Serbanescu et al, 2016 ; Xie et al, 2019 ), B cells ( Hotchkiss et al, 2001 ; Sjaastad et al, 2018 ; Unsinger et al, 2010 ), NK cells ( Hou et al, 2014 ; Jensen et al, 2021b ; Jensen et al, 2018b ; Souza-Fonseca-Guimaraes et al, 2012 ), and dendritic cells (DCs) ( Poehlmann et al, 2009 ; Roquilly et al, 2017 ; Strother et al, 2016 ). We and others have characterized numerous impairments early after sepsis induction; however, the extent to which those cell populations recover in number and function remains largely unknown.…”

Sepsis impedes EAE disease development and diminishes autoantigen-specific naive CD4 T cells

“…While there is a dearth of knowledge regarding the impact of sepsis on autoimmunity, descriptions of how sepsis influences specific cell subsets can provide insight into how autoimmune disease may be influenced. With regard to the critical role for CD4 T cells in EAE disease, the sepsis-induced lymphopenic state is known to impact both naive and memory CD4 T cells ( Cabrera-Perez et al, 2016 ; Cabrera-Perez et al, 2015 ; Chen et al, 2017 ; Jensen et al, 2018a ; Sjaastad et al, 2020b ). In particular, sepsis can diminish the number of naive CD4 T cell precursors subsequently limiting the number of cells capable of responding to a given antigen ( Cabrera-Perez et al, 2015 ; Martin et al, 2020 ).…”