title: Transcriptional profiling of innate and adaptive human immune responses to mycobacteria in the tuberculin skin test.
abstract: The tuberculin skin test (TST) is a model of integrated innate and adaptive human immune responses to Mycobacterium tuberculosis, but the component processes that are involved in this model have not previously been defined in vivo. We used transcriptional profiling to study these responses within the TST at molecular and system levels. Skin biopsies from TST injection sites were examined in subjects classified as TST(+)  or TST(-)  by clinical and histological criteria. Genome-wide expression arrays showed evolution of immune responses reflecting T-cell activation and recruitment with uniquely Th1-polarized responses and cytotoxic T cells (CTLs). In addition, distinct innate immune and IFN-γ-stimulated gene expression signatures were identified, under the regulation of NF-κB and STAT1 transcriptional control. These were highly enriched for chemokines and MHC class II molecules providing a potential mechanism for paracrine amplification of inflammatory responses in the TST, by supporting cellular recruitment and enhancing antigen presentation. The same repertoire of innate and adaptive immune responses was evident in TST(+)  and TST(-)  subjects alike, clinically positive TSTs being distinguished only by quantitatively greater differences. These data provide new insights into complex multifaceted responses within the TST, with much greater sensitivity than previous clinical or histological assessments.
authors.affiliation: Infection and Immunity, University College London, London, UK.
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Tomlinson
authors.forename: Tamaryn J
authors.initials: TJ
authors.lastname: Cashmore
authors.forename: Paul T G
authors.initials: PT
authors.lastname: Elkington
authors.forename: John
authors.initials: J
authors.lastname: Yates
authors.forename: Rannakoe J
authors.initials: RJ
authors.lastname: Lehloenya
authors.forename: Jhen
authors.initials: J
authors.lastname: Tsang
authors.forename: Michael
authors.initials: M
authors.lastname: Brown
authors.forename: Robert F
authors.initials: RF
authors.lastname: Miller
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
authors.forename: David R
authors.initials: DR
authors.lastname: Katz
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Chain
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics* / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics*; D009161:Mycobacterium / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014374:Tuberculin Test; D014376:Tuberculosis / Q000276:immunology