title: Th1-skewed tissue responses to a mycolyl glycolipid in mycobacteria-infected rhesus macaques.
abstract: Trehalose 6,6'-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette-Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.
authors.affiliation: Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morita
authors.forename: Ayumi
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Takaya
authors.initials: T
authors.lastname: Komori
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Igarashi
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugita
mesh_terms: D000818:Animals; D018925:Chemokines / Q000097:blood; D006017:Glycolipids / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D008253:Macaca mulatta / Q000097:blood / Q000276:immunology* / Q000382:microbiology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008954:Models, Biological; D009161:Mycobacterium / Q000276:immunology*; D009164:Mycobacterium Infections / Q000097:blood / Q000276:immunology / Q000382:microbiology*; D009928:Organ Specificity / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D018925:Chemokines; D006017:Glycolipids; C048938:glucose mycolate; D007371:Interferon-gamma
keywords: Ag; BCG; GMM; Glucose monomycolate; Mycobacterium bovis bacillus Calmette–Guerin; Rhesus macaques; TDM; Tuberculosis; antigen; glucose monomycolate; trehalose 6,6′-dimycolate