Scriba, T. J. | Search bioRxiv

bioRxiv2017

Cytomegalovirus infection is a risk factor for TB disease in Infants

Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first two years of life, and 129 matched controls who remained healthy, we found the cytomegalovirus (CMV) stimulated IFN-{gamma} response at age 4-6 months to be associated with CD8+ T-cell activation (Spearmans rho, p=6x10-8). A CMV specific IFN-{gamma} response was also associated with increased risk of developing TB disease (Conditional Logistic Regression, p=0.043, OR 2.2, 95% CI 1.02-4.83), and shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.037). CMV positive infants who developed TB disease had lower expression of natural killer cell associated gene signatures and a lower frequency of CD3-CD4-CD8-lymphocytes. We identified transcriptional signatures predictive of risk of TB disease among CMV ELISpot positive (AUROC 0.98, accuracy 92.57%) and negative (AUROC 0.9, accuracy 79.3%) infants; the CMV negative signature validated in an independent infant study (AUROC 0.71, accuracy 63.9%). Understanding and controlling the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

immunology↗

bioRxiv2017

Unbiased Definition Of A Shared T-Cell Receptor Motif Enables Population-Based Studies Of Tuberculosis

Peptide-specific T cells that are restricted by highly polymorphic major histocompatibility complex (MHC) proteins express diverse T-cell receptors (TCRs) that are rarely shared among unrelated individuals. T-cells can also recognize bacterial lipid antigens that bind the relatively non-polymorphic CD1 family of proteins. However, genetic variation in human CD1 genes and TCR diversity expressed by CD1-restricted T-cells have not been quantitatively determined. Here, we show that CD1B is nearly nucleotide-identical across all five continental ancestry groups, providing evidence for purifying selection during human evolution. We used CD1B tetramers loaded with a mycobacterial glycolipid antigen to isolate T-cells from four genetically unrelated South African adults and cataloged thousands of TCRs from in-vitro expanded T-cells using immunosequencing. We identified highly conserved motifs that were co-expressed as a functional heterodimer and significantly enriched among tetramer-positive T-cells sorted directly from peripheral blood. Finally, we show that frequencies of these TCR motifs are increased in the blood of patients with active tuberculosis compared to uninfected controls, a finding that is confirmed by ex-vivo frequencies of tetramer-positive T-cells determined by flow cytometry. These data provide a framework for unbiased definition of TCRs targeting lipid antigens, which can be tested for clinical associations independently of host genetic background.\n\nBrief SummaryWe used human genetics and immunosequencing to define a shared T-cell receptor motif that is specific for a mycobacterial lipid antigen and associated with tuberculosis independently of host genetic background.

immunology↗