title: Mycobacterium tuberculosis impairs dendritic cell functions through the serine hydrolase Hip1.
abstract: Mycobacterium tuberculosis is a highly successful human pathogen that primarily resides in host phagocytes, such as macrophages and dendritic cells (DCs), and interferes with their functions. Although multiple strategies used by M. tuberculosis to modulate macrophage responses have been discovered, interactions between M. tuberculosis and DCs are less well understood. DCs are the primary APCs of the immune system and play a central role in linking innate and adaptive immune responses to microbial pathogens. In this study, we show that M. tuberculosis impairs DC cytokine secretion, maturation, and Ag presentation through the cell envelope-associated serine hydrolase, Hip1. Compared to wild-type, a hip1 mutant strain of M. tuberculosis induced enhanced levels of the key Th1-inducing cytokine IL-12, as well as other proinflammatory cytokines (IL-23, IL-6, TNF-α, IL-1β, and IL-18) in DCs via MyD88- and TLR2/9-dependent pathways, indicating that Hip1 restricts optimal DC inflammatory responses. Infection with the hip1 mutant also induced higher levels of MHC class II and costimulatory molecules CD40 and CD86, indicating that M. tuberculosis impairs DC maturation through Hip1. Further, we show that M. tuberculosis promotes suboptimal Ag presentation, as DCs infected with the hip1 mutant showed increased capacity to present Ag to OT-II- and early secreted antigenic target 6-specific transgenic CD4 T cells and enhanced Th1 and Th17 polarization. Overall, these data show that M. tuberculosis impairs DC functions and modulates the nature of Ag-specific T cell responses, with important implications for vaccination strategies.
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30329;
authors.forename: Ranjna
authors.initials: R
authors.lastname: Madan-Lala
authors.forename: Jonathan Kevin
authors.initials: JK
authors.lastname: Sia
authors.forename: Rebecca
authors.initials: R
authors.lastname: King
authors.forename: Toidi
authors.initials: T
authors.lastname: Adekambi
authors.forename: Leticia
authors.initials: L
authors.lastname: Monin
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.forename: Jyothi
authors.initials: J
authors.lastname: Rengarajan
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; C489536:Hip1 protein, mouse