Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world?s population and kills over a million people annually. Although it is known that CD4 T cells and interferon (IFN)? are crucial for defense against Mtb, a general lack of understanding of how this response is regulated has thus far hampered successful vaccine development. Our lab focuses on the CD4 T cell response to two immunodominant Mtb antigens: ESAT6, which is expressed continuously, and Ag85B, which is expressed only during bacterial replication. We have found that differential exposure of these T cells to their cognate antigens in the lung results in functional exhaustion of ESAT6-specific T cells but not Ag85B-specific T cells. An unbiased bioinformatics approach predicted vitamin D receptor (VDR) as a regulator of a subset of genes that are enriched in Ag85B-specific T cells, leading us to investigate the role of T cell VDR signaling during Mtb infection. Indeed, VDR deficiency had differential effects on Mtb-specific CD4 T cells in an in vivo mouse infection model: ESAT6-specific T cells failed to expand, yet Ag85B-specific T cells had enhanced IFN? production. These results have interesting implications for Mtb therapeutics because low vitamin D levels have long been associated with increased susceptibility to disease, although the role of vitamin D signaling in T cells has never been explored in the context of tuberculosis. The central hypothesis of this proposal is that VDR signaling in both T cells and macrophages plays an essential role in protection from tuberculosis. This hypothesis will be tested using a combination of systems biology and cellular immunology approaches. More specifically, Aim 1 will seek to identify VDR target genes of ESAT6- and Ag85B-specific T cells by comparison of WT and VDR-/- T cell transcriptomes using RNA-seq.
Aim 2 will address the question of how VDR is controlling the maintenance of Mtb-specific T cells and whether it is indeed dependent on antigen availability. Finally, Aim 3 will use T cell-specific VDR knockout mice and mixed bone marrow chimeras to simultaneously assess the contributions of myeloid cells and T cells to vitamin D-mediated protection. Combined, the studies proposed here will reveal the molecular networks targeted by vitamin D and elucidate how T cell VDR signaling influences the outcome of Mtb infection.

Public Health Relevance

Mycobacterium tuberculosis (Mtb) kills over a million people annually, and a general misunderstanding of the immune response has thus far hampered the development of host-directed therapies. This proposal seeks to unravel the role of vitamin D in regulating different T cell populations in the lung during Mtb infection. Identifying a role for vitamin D in controlling protective T cell responses could inform rational therapeutic approaches to combat disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI126703-02
Application #
9446771
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Eichelberg, Katrin
Project Start
2017-03-01
Project End
2019-06-30
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109