T cells play a critical role in the host response to Mtb infection, and are their antigen specificity forms the basis of widely used clinical immunodiagnostic tests. MHC-restricted effector memory T cells protect the host from progression to active TB disease, but the particular effector functions, which mediate control are unknown. In a well characterized human patient cohort in Lima, Peru, we will determine the association of active TB disease with 400 transcripts measured in highly purified effector memory T cells. Transcripts associated with lack of disease progression will be validated by PCR and protein measurements to define gene products that can be measured as surrogates for protection from TB progression and targets for immunotherapy development. Nearly all current technology development efforts related to adjuvant formulation, vaccine design and immunodiagnosis focus on MHC antigen presenting molecules. However, recent studies show that non-classical CDIb and MRI proteins present mycobacterial lipids and metabolites to T cells in TB disease. Emphasizing new ex vivo methods and CD1 tetramers, we will measure the relationship of expansion of lipid- and metabolite-specific GEM T cells and MAIT cells during human and guinea pig infection and relapse. In particular, we propose to (a) measure GEM T cell expansion ex vivo during acute human tuberculosis infection (b) comparative nanostring profiling of effector functions of MAIT cells and GEM T cells, and (c) detect CDIb-restricted T cells in guinea pigs using CDIb tetramers. These translational studies seek to establish the first tractable small animal model of in vivo CDIb function and detect a causal relationship of infection with invariant T cell activation. Bypassing the genetic complexities of human MHC proteins, activation of invariant T cells by lipids and metabolites offers potentially more uniform outcomes that could be detected or modulated with lipids and vitamin metabolites (Project 4).

Public Health Relevance

This project seeks to investigate the role of effector functions in T-cell subsets to understand which genes in the broader population might predispose certain individuals to tuberculosis or form the basis of therapy. This innovative approach investigates T cell function beyond basic immunological classifications, which have already been shown to play a crucial role in tuberculosis infection risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111224-07
Application #
10089387
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2015-02-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
James, Charlotte A; Yu, Krystle K Q; Gilleron, Martine et al. (2018) CD1b Tetramers Identify T Cells that Recognize Natural and Synthetic Diacylated Sulfoglycolipids from Mycobacterium tuberculosis. Cell Chem Biol 25:392-402.e14
Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin et al. (2018) Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9:789
Davenport, Emma E; Amariuta, Tiffany; Gutierrez-Arcelus, Maria et al. (2018) Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial. Genome Biol 19:168
Carette, Xavier; Platig, John; Young, David C et al. (2018) Multisystem Analysis of Mycobacterium tuberculosis Reveals Kinase-Dependent Remodeling of the Pathogen-Environment Interface. MBio 9:
Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup et al. (2018) An Antibacterial ?-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis. Angew Chem Int Ed Engl 57:348-353
Wun, Kwok S; Reijneveld, Josephine F; Cheng, Tan-Yun et al. (2018) T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nat Immunol 19:397-406
Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M et al. (2017) A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell 170:973-985.e10
Moody, D Branch (2017) How T cells grasp mycobacterial lipid antigens. Proc Natl Acad Sci U S A 114:13312-13314
Brennan, Patrick J; Cheng, Tan-Yun; Pellicci, Daniel G et al. (2017) Structural determination of lipid antigens captured at the CD1d-T-cell receptor interface. Proc Natl Acad Sci U S A 114:8348-8353
Rao, Deepak A; Gurish, Michael F; Marshall, Jennifer L et al. (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542:110-114

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