DOI

10.17077/etd.i1rj-oix2

Document Type

Dissertation

Date of Degree

Summer 2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Badovinac, Vladimir P.

First Committee Member

Harty, John T.

Second Committee Member

Varga, Steven M.

Third Committee Member

Legge, Kevin L.

Fourth Committee Member

Xue, Hai-Hui

Abstract

Sepsis occurs when infection enters the circulation resulting in harmful or lethal levels of pro- and anti-inflammatory cytokines that affects nearly 2 million people in the U.S. annually. Improved identification and treatment options have increased survival of patients shortly after sepsis. However, this management of sepsis subsequently revealed survivors have increased long-term mortality rates due to altered immune responses that increase susceptibility to secondary complications. My thesis further revealed how sepsis impacts CD8 T cell-mediated immunity that protects the host against sepsis unrelated complications that will be useful for improving the outcome of sepsis survivors.

Using vaccinia virus (VacV) to generate circulating (TCIRCM) and skin resident (TRM) memory CD8 T cells, I showed sepsis preferentially diminishes the number and function of TCIRCM, while TRM in barrier tissues were unaffected in mice that received a low-severity model of sepsis. Despite optimal number and ‘sensing and alarming’ function of skin TRM, the capacity of these cells to promote a tissue-wide recall response was lost after sepsis that increased viral burden upon homologous skin infection. Decreased sensitivity of vascular endothelium to TRM-derived IFN-γ was the underlying mechanism that diminished localized recall responses after sepsis. Overall, my data stress the importance of understanding how sepsis-induced lesions in T cell-extrinsic factors contribute to diminished T cell-mediated immunity observed after sepsis.

Sepsis influence on T cell-mediated immunity has previously been explored using model pathogens. However, sepsis survivors are susceptible to an array of secondary complications, including cancer, which often occurs in patients with no previous history of malignancy. This suggested the immunoparalysis phase of sepsis increases cancer incidence and/or progression that may contribute to the increased long-term mortality of this population. I showed that previously-septic mice had increased cancer-associated mortality weeks/months after sepsis recovery due to diminished frequency and function of tumor-infiltrating CD8 T cells (CD8 TILs) that mediate partial control of B16 melanoma. CD8 T cells with high expression of inhibitory receptors (denoted PD-1hi) that retain some effector functions in the tumor were preferentially eliminated in sepsis survivors. The rapid loss of PD-1hi CD8 TILs diminished the window of efficacy for checkpoint blockade therapy designed to improve the number and function of this T cell subset. Thus, the chronic immunoparalysis phase of sepsis is defined by diminished tumor-specific CD8 T cell responses that increases susceptibility to cancer mortality.

Most sepsis patients have comorbidities at the time of sepsis onset but the capacity of sepsis to influence comorbidity burden remains unknown. Because cancer is the highest risk factor for sepsis, I examined the capacity of sepsis to influence the outcome of hosts bearing solid tumors. Sepsis was performed after B16 inoculation and recapitulated clinical data showing increased sepsis mortality in cancer patients. However, sepsis mortality only occurred in mice bearing large tumors, while hosts with less progressed tumors survived the septic event and had improved cancer prognosis. CD8 T cells were required for this phenomenon and the number of vasculature-excluded CD8 TILs was not altered after sepsis. Despite this, I showed CD8 TILs from mice that survived sepsis had increased activation and effector functions suggesting sepsis has the unexpected capacity to reinvigorate this subset. In total, sepsis impact on CD8 T cell responses alters host outcome to additional disease states that commonly affect sepsis patients, a notion that will be important for a growing number of sepsis survivors.

Pages

xiii, 215 pages

Bibliography

Includes bibliographical references (pages 189-215).

Copyright

Copyright © 2019 Derek Brett Danahy

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