title: Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis.
abstract: Transient lymphopenia is one hallmark of sepsis, and emergent data indicate the CD4 T cell compartment in sepsis survivors is numerically and functionally altered (when examined at the Ag-specific level) compared with nonseptic control subjects. Previous data from our laboratory demonstrated Ag-independent, lymphopenia-induced homeostatic proliferation to be a contributing mechanism by which CD4 T cells numerically recover in sepsis survivors. However, we reasoned it is also formally possible that some CD4 T cells respond directly to Ag expressed by gut-resident microbes released during polymicrobial sepsis. The effect of gut microbiome leakage on CD4 T cells is currently unknown. In this study, we explored the number and function of endogenous CD4 T cells specific for segmented filamentous bacterium (SFB) after cecal ligation and puncture (CLP)-induced sepsis using mice that either contained or lacked SFB as a normal gut-resident microbe. Interestingly, SFB-specific CD4 T cells underwent Ag-driven proliferation in CLP-treated SFB(+), but not in SFB(-), mice. Moreover, CLP-treated SFB(+) mice showed resistance to secondary lethal infection with recombinant SFB Ag-expressing virulent Listeria (but not wild-type virulent Listeria), suggesting the CLP-induced polymicrobial sepsis primed for a protective response by the SFB-specific CD4 T cells. Thus, our data demonstrate that the numerical recovery and functional responsiveness of Ag-specific CD4 T cells in sepsis survivors is, in part, modulated by the intestinal barrier's health discreetly defined by individual bacterial populations of the host's microbiome.
authors.affiliation: Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455; Medical Scientist Training Program, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Javier
authors.identifier: 0000-0002-5408-3820
authors.initials: J
authors.lastname: Cabrera-Perez
authors.affiliation: Medical Student Summer Research Program in Infection and Immunity, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Babcock
authors.affiliation: Center for Immunology, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Thamotharampillai
authors.identifier: 0000-0002-2810-6996
authors.initials: T
authors.lastname: Dileepan
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Murphy
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Kucaba
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242; Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242;
authors.forename: Vladimir P
authors.identifier: 0000-0003-3180-2439
authors.initials: VP
authors.lastname: Badovinac
authors.affiliation: Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455; Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Department of Urology, University of Minnesota, Minneapolis, MN 55455; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455; and Minneapolis VA Health Care System, Minneapolis, MN 55417 tgriffit@umn.edu.
authors.forename: Thomas S
authors.identifier: 0000-0002-7205-9859
authors.initials: TS
authors.lastname: Griffith
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002432:Cecum / Q000601:surgery; D005434:Flow Cytometry; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D007422:Intestines / Q000382:microbiology; D008087:Listeria / Q000737:chemistry / Q000276:immunology / Q000472:pathogenicity; D008231:Lymphopenia / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology*
chemical_list: D000942:Antigens, Bacterial