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Commensal-host Interactions Calibrate Systemic Immune Responsiveness

Jiang, Tianlun T
http://orcid.org/0000-0003-4979-0974
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1529334295910701

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Immunology.
The protective benefits of commensal bacteria in positively calibrating the responsiveness of systemic immune cells to bolster antiviral immunity is now increasingly recognized. However, key gaps in knowledge remain regarding the broader applicability of this immune modulation to other pathogen types, and whether non-bacterial commensal microbial species share similar beneficial roles. Here we show that in contrast to dampened antiviral immunity, commensal bacteria eradication bolsters protection against disseminated Candida albicans fungal infection by unleashing neutrophil mobilization and accumulation. This discordance in how commensal bacteria control antifungal compared with antiviral immunity highlights intrinsic differences in responsiveness for distinct immune cell subsets. For example, we show pathogen-specific CD8 T cells that protect against viruses are suppressed after either fungal C. albicans or viral influenza A infection in the absence of intestinal bacteria. Furthermore, the protective benefits of enteric bacteria in averting mortality induced by viral infection or local tissue injury are each recapitulated by diverse strains of commensal fungi that commonly colonize the mammalian intestinal tract. Using antigen-specific tools to characterize how endogenous T cells respond to commensal fungi revealed the systemic accumulation of a new lineage of fungal-specific KLF2+CD44+ CD4 T cells that have potent suppressive properties in vitro. This lineage of suppressive CD4 T cells may play fundamental roles in restraining proliferation of effector T cells with commensal specificity to avert immunopathology such as inflammatory bowel disease. Interestingly, tolerance to commensal fungi may also require cell intrinsic regulation as commensal-specific CD4 T cells were also enriched for expression of the inhibitory molecule programmed death-1 (PD-1). Given the necessity we show for PD-1 in silencing the activation of high-affinity self-reactive CD4 T cells to avert autoimmunity, these findings suggest that tolerance to both self and commensal antigens may share a common regulatory pathway. Collectively, these findings have exciting potential to expose new strategies for therapeutically modifying the in vivo balance between immune stimulation and suppression.
Sing Sing Way, Ph.D. (Committee Chair)
Theresa Alenghat, Ph.D. (Committee Member)
George Deepe, M.D. (Committee Member)
Gurjit Khurana Hershey, M.D. (Committee Member)
Marc Rothenberg, M.D. Ph.D. (Committee Member)
132 p.
Immunology
commensal fungi; commensal bacteria; commensal microbe; influenza A; LPS; mannan

Recommended Citations

Citations

  • Jiang, T. T. (2017). Commensal-host Interactions Calibrate Systemic Immune Responsiveness [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1529334295910701

    APA Style (7th edition)

  • Jiang, Tianlun. Commensal-host Interactions Calibrate Systemic Immune Responsiveness. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1529334295910701.

    MLA Style (8th edition)

  • Jiang, Tianlun. "Commensal-host Interactions Calibrate Systemic Immune Responsiveness." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1529334295910701

    Chicago Manual of Style (17th edition)

ucin1529334295910701
191
© 2017, some rights reserved.Creative Commons License Commensal-host Interactions Calibrate Systemic Immune Responsiveness by Tianlun T Jiang is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.