Molecular profiling of the tuberculin skin test to model immune responses to Mycobacterium tuberculosis
Summary
Tuberculin is a standardised clinical grade preparation of a protein-enriched fraction of heat-killed Mycobacterium tuberculosis (Mtb). Its intrademal injection in people who have been previously exposed to Mtb leads to focal inflammatory induration that provides a prototypic model of cell mediated immunity (Type IV delayed-type hypersensitivity), dependent on adaptive T cell memory. The TST has been used for almost 100 years to identify individuals with T cell reactivity to Mtb as surrogate for previous infection.
Transcriptional profiling of tissue biopsies from the site of the TST reveals enrichment of multiple immune response signaling pathways associated with both innate and adaptive immunity. Single cell and TCR sequencing offers opportunities to identify clonal and functional repertoire of T cell responses and inter-cellular molecular interactions.The TST model offers an invaluable approach for standardised evaluation of molecular, cellular and systems level assessment of dynamic in vivo immune responses that overcomes the limitations of steady state measurements in people with disease, and the sampling error in ex vivo immune stimulation in peripheral blood samples.
We have used transcriptional profiling of the TST to provide evidence for a potential host-protective role for type 1 interferon responses in pulmonary TB, and to identify potential mechanisms of TB immunopathogenesis amenable to therapeutic targeting. Specifically, exaggerated Th2 responses in HIV-associated TB immune reconstitution inflammatory disease, and exaggerated IL-17 activity in HIV‑negative individuals with TB. This model continues to be an important experimental approach in ongoing work.
Publications
Turner CT, Rosenheim J, Thakker C, Chandran A, Wilson H, Venturini C, Pollara G, Chain BM, Tomlinson GS, Noursadeghi M. Single-cell transcriptome and T cell receptor profiling of the tuberculin skin test. bioRxiv. June 2024:2024.06.25.600676. doi:10.1101/2024.06.25.600676.
Szydlo-Shein A, Estrada BS-MD de, Rosenheim J, Turner CT, Tsaliki E, Lipman MCI, Kunst H, Pollara G, Elks PM, Levraud J-P, Payne EM, Noursadeghi M, Tomlinson GS. Type I interferon responses contribute to immune protection against mycobacterial infection. medRxiv. June 2024. doi:10.1101/2024.06.26.24309490.
Pollara G, Turner CT, Rosenheim J, Chandran A, Bell LCK, Khan A, Patel A, Peralta LF, Folino A, Akarca A, Venturini C, Baker T, Ecker S, Ricciardolo FLM, Marafioti T, Ugarte-Gil C, Moore DAJ, Chain BM, Tomlinson GS, Noursadeghi M. Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease. Science Translational Medicine. 2021;13(592). doi:10.1126/scitranslmed.abg7673.
Byng-Maddick R, Turner CT, Pollara G, Ellis M, Guppy NJ, Bell LCK, Ehrenstein MR, Noursadeghi M. Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy. Front Immunol. 2017;8. doi:10.3389/fimmu.2017.00932.
Bell LCK, Pollara G, Pascoe M, Tomlinson GS, Lehloenya RJ, Roe J, Meldau R, Miller RF, Ramsay A, Chain BM, Dheda K, Noursadeghi M. In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis. PLoS Pathog. 2016;12(3):e1005469. doi:10.1371/journal.ppat.1005469.
Tomlinson GS, Cashmore TJ, Elkington PTG, Yates J, Lehloenya RJ, Tsang J, Brown M, Miller RF, Dheda K, Katz DR, Chain BM, Noursadeghi M. Transcriptional profiling of innate and adaptive human immune responses to mycobacteria in the tuberculin skin test. Eur J Immunol. 2011;41(11):3253-3260. doi:10.1002/eji.201141841.