Project Details

Mucosal invariant T cells and their memory potential – how they may be crucial in future tuberculosis vaccine development

Dylan Kain, MD

Summary

BACKGROUND: With 1.6 million deaths in 2021, including 230,000 in children, tuberculosis (TB) is the number one infectious cause of mortality worldwide. Better understanding of the immunological response to infection is needed, especially in children to help inform future vaccine development. GAP: MR1-restricted (MR1) T cells are a relatively novel subset of T cells that respond robustly and rapidly to bacterial metabolites produced by several childhood pathogens, including Mycobacterium tuberculosis (Mtb), the etiology of TB. In order to understand if these cells can be harnested in future vaccine development, we must first determine if they have features of immunological immunity. HYPOTHESIS: We hypothesize that MR1T cells possess immunological memory. Furthermore we hypothesize that BCG vaccination will lead to MR1T cells that possess more cytotoxic and pro-inflammatory potential. METHODS: The study will utilize a biorepository of South African clinical samples. There are three comparison groups; cord blood samples at birth, infants at 9-weeks of age who received a BCG vaccine (a mycobacterial antigen exposure) at birth, and a third group at 9-weeks who had their BCG vaccine delayed until after blood samples were collected at 9-weeks of age. From these samples, MR1T cells will be sorted out and then we will perform scGEXseq and scTCRseq to obtain single cell transcriptional and TCR expression profiles, respectively. If MR1T cells possess immunological memory, we expect to see selective expansion of TCR usage in the 9-week old vaccinated group compared to the un-vaccinated group. This would suggest that certain MR1T cells that recognize mycobacterial antigens expand in response to these antigens, and persist for 9 weeks. If there is selective TCR usage, this can then be compared to the gene expression to see if these cells possess certain gene signatures, such as cytotoxic or memory ones. RESULTS: Pending. IMPACT: Novel approaches for TB vaccine development are needed to protect children. Given the robust and rapid anti-mycobacterial response of MR1T cells and their enrichment in the lungs, they represent an exciting opportunity for future TB vaccine development. In order to utilize these cells to their potential, we must first understand if they possess immunological memory, and our project will set out to answer this question. Website Link: https://www.ohsu.edu/school-of-medicine/pulmonary-critical-care-medicine/david-lewinsohn-lab