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

• Published in: Frontiers in immunology Vol. 11; p. 1786
• Main Authors: Sjaastad, Frances V, Kucaba, Tamara A, Dileepan, Thamotharampillai, Swanson, Whitney, Dail, Cody, Cabrera-Perez, Javier, Murphy, Katherine A, Badovinac, Vladimir P, Griffith, Thomas S
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12.08.2020
• Subjects: Animals; Antigens, Bacterial - immunology; CD4 T cells; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - microbiology; Cecum - microbiology; Cecum - surgery; Cell Proliferation; Coinfection - immunology; Coinfection - metabolism; Coinfection - microbiology; Cytokines - metabolism; Disease Models, Animal; Female; Host-Pathogen Interactions; IFN-gamma; immune suppression; Immunity, Cellular; Immunologic Memory; Immunology; Ligation; Listeria monocytogenes - immunology; Listeria monocytogenes - pathogenicity; Listeriosis - immunology; Listeriosis - metabolism; Listeriosis - microbiology; Lymphocyte Activation; memory; Mice, Inbred C57BL; Punctures; Salmonella enterica - immunology; Salmonella enterica - pathogenicity; Salmonella Infections - immunology; Salmonella Infections - metabolism; Salmonella Infections - microbiology; sepsis; Sepsis - immunology; Sepsis - metabolism; Sepsis - microbiology; CD4 T cells; memory; IFN-gamma; immune suppression; sepsis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.01786

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 (Lm) expressing the I-A -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 2W ( -2W) 30 days before sham or CLP surgery, and then challenged with virulent 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 -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.