Wong, Eileen
(2018)
MODULATION OF T CELL RESPONSE IN TUBERCULOSIS GRANULOMAS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Tuberculosis (TB) remains a major threat to global health. When an individual is infected with M. tuberculosis (Mtb), the causative agent of TB, host immune cells form highly organized structures, granulomas, around the bacteria. Granulomas contain Mtb and prevent dissemination, but can also serve as a niche for persistence. While host control of Mtb infection involves an interplay of innate and adaptive immune cells in the granulomas, T cells have been demonstrated to be a critical component. The goal of this dissertation was to define facets of the host immune system that modulate the T cell cytokine response in TB granulomas and ways to alter the T cell cytokine responses to improve protection through vaccination, by using a non-human primate (NHP) model that recapitulates human TB disease and granuloma formation. In the first aim, the role of IL-10 in downregulating T cell responses in granulomas was investigated by neutralization of IL-10 in Mtb-infected NHPs. Although lack of IL-10 had a transiently increased the immune response early in Mtb infection (4 weeks), the presence or absence of IL-10 did not affect the overall inflammation, bacterial burden, or disease pathology up to 8 weeks post-infection. The second aim examined T cell exhaustion in TB granulomas by characterizing expression of the inhibitory receptors PD-1, CTLA-4, and LAG-3 on T cells. Low levels of expression of the inhibitory receptors suggested few exhausted T cells in granulomas. Moreover, T cells expressing inhibitory receptors were still functional and capable of proliferation, indicating that these inhibitory receptors may not be a marker of exhaustion in TB. Finally, the third aim investigated vaccination strategies to alter granuloma T cell response and confer protection from TB disease. While none of the experimental vaccination strategies were more protective than the current vaccine BCG, some of the strategies increased T cell cytokine response in granulomas. In summary, the factors investigated in this dissertation were not significant contributors to the modulation of T cell responses or Mtb control in TB granulomas, but these results further inform the field of the immune response to Mtb for potential future vaccines and therapeutics.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
6 July 2018 |
| Date Type: |
Publication |
| Defense Date: |
15 May 2018 |
| Approval Date: |
6 July 2018 |
| Submission Date: |
5 July 2018 |
| Access Restriction: |
3 year -- Restrict access to University of Pittsburgh for a period of 3 years. |
| Number of Pages: |
241 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Molecular Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
tuberculosis, Mycobacterium tuberculosis, granuloma, IL-10, PD-1, CTLA-4, LAG-3, T cell exhaustion, vaccine, immunomodulation, prime-boost |
| Date Deposited: |
06 Jul 2018 17:54 |
| Last Modified: |
06 Jul 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/34847 |
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