The Impact of Sepsis on CD8 T Cells

Sepsis is characterized by a systemic infection resulting in organ failure. Sepsis related complications currently account for 33-50% of all hospital deaths. Patients that survive a septic event are more susceptible to infection. The Badovinac lab focuses on CD8 T cells which provide protection against viral and bacterial infections. Our lab has shown that sepsis leads to cell death of both naïve and memory CD8 T cells resulting in increased susceptibility to new, or previously encountered infections.

Tissue-resident memory (TRM) is a recently discovered CD8 T cell subset. These cells survey barrier tissues that are commonly exploited by pathogens to enter the host and cause infection. During a localized infection, TRM rapidly provide protection by recruiting and activating immune cells at the site of pathogen entry. It is not currently known the extent to which sepsis affects TRM. I will start addressing this by elucidating the impact of sepsis on TRM numbers, metabolism and protective capacity.

Huggins MA, Sjaastad FV, Pierson M, Kucaba TA, Swanson W, Staley C, Weingarden AR, Jensen IJ, Danahy DB, Badovinac VP, Jameson SC, Vezys V, Masopust D, Khoruts A, Griffith TS, Hamilton SE. Microbial Exposure Enhances Immunity to Pathogens Recognized by TLR2 but Increases Susceptibility to Cytokine Storm through TLR4 Sensitization. Cell Rep. 2019 Aug 13;28(7):1729-1743.e5. doi: 10.1016/j.celrep.2019.07.028. PubMed PMID: 31412243; PubMed Central PMCID: PMC6703181.

Danahy DB, Kurup SP, Winborn CS, Jensen IJ, Harty JT, Griffith TS, Badovinac VP. Sepsis-Induced State of Immunoparalysis Is Defined by Diminished CD8 T Cell-Mediated Antitumor Immunity. J Immunol. 2019 Jun 12. pii: ji1900435. doi:10.4049/jimmunol.1900435. [Epub ahead of print] PubMed PMID: 31189573.

Danahy DB, Jensen IJ, Griffith TS, Badovinac VP. Cutting Edge: Polymicrobial Sepsis Has the Capacity to Reinvigorate Tumor-Infiltrating CD8 T Cells and Prolong Host Survival. J Immunol. 2019 Apr 10. pii: ji1900076. doi:10.4049/jimmunol.1900076. [Epub ahead of print] PubMed PMID: 30971442.

Sjaastad FV, Condotta SA, Kotov JA, Pape KA, Dail C, Danahy DB, Kucaba TA, Tygrett LT, Murphy KA, Cabrera-Perez J, Waldschmidt TJ, Badovinac VP, Griffith TS. Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses. Front Immunol. 2018 Oct 31;9:2532. doi: 10.3389/fimmu.2018.02532. eCollection 2018. PubMed PMID: 30429857; PubMed Central PMCID: PMC6220049.

Martin MD, Danahy DB, Hartwig SM, Harty JT, Badovinac VP. Revealing the Complexity in CD8 T Cell Responses to Infection in Inbred C57B/6 versus Outbred Swiss Mice. Front Immunol. 2017 Nov 22;8:1527. doi: 10.3389/fimmu.2017.01527. eCollection 2017. PubMed PMID: 29213267; PubMed Central PMCID: PMC5702636.

Danahy DB, Anthony SM, Jensen IJ, Hartwig SM, Shan Q, Xue H-H, et al. (2017) Polymicrobial sepsis impairs bystander recruitment of effector cells to infected skin despite optimal sensing and alarming function of skin resident memory CD8 T cells. PLoS Pathog 13(9): e1006569. https://doi.org/10.1371/journal. ppat.1006569

Strother RK, Danahy DB, Kotov DI, Kucaba TA, Zacharias ZR, Griffith TS, Legge KL, Badovinac VP. Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo. J Immunol. 2016 Dec 1;197(11):4301-4311. PubMed PMID: 27798171; PubMed Central PMCID: PMC5123856.

Danahy DB, Strother RK, Badovinac VP, Griffith TS. Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity. Crit Rev Immunol. 2016;36(1):57-74. doi:10.1615/CritRevImmunol.2016017098. PubMed PMID: 27480902; PubMed Central PMCID: PMC5314458.

Honors and Awards

• Graduate College Summer Fellowship, Summer 2018
• Selected speaker at CEPS CGP Collaborative Retreat, 2018
• Graduate College Post-Comprehensive Research Award, Spring 2017
• Selected speaker at Immunology & Immune-Based Diseases Research Retreat, 2016
• National Institutes of Health – Predoctoral Training Grant T32 AI007485, 2018
• U. Iowa College of Medicine – Trainee Scholar Travel Award, 2018
• U. Iowa Holden Comprehensive Cancer Center – Oberley Grant, 2018
• The Annual Conference on Shock Travel Award, 2019
• NIAID T32 Predoctoral Training Grant AI007485 2018-2019