Cellular & Molecular Immunology 7, 316-322 (July 2010) | doi:10.1038/cmi.2010.7
Glucocorticoid-induced tumor-necrosis factor receptor (GITR) and its ligand, GITRL, play significant roles in regulating immune responses. It is clear that human soluble GITRL (hsGITRL) transduces signal activity through multiple oligomerization states. To develop human soluble trimeric GITRL protein as a potential therapeutic target, we explored the link of the isoleucine-zipper (ILZ) motif to the N-terminus of the human soluble GITRL with two leucine sequences. hsGITRL, with the ILZ motif (ILZ-hsGITRL), was firstly expressed in Escherichia coli, which exhibited a predominant trimer when identified by Sephadex G-100 filtration and non-reducing SDS–polyacrylamide gel electrophoresis (SDS-PAGE). The significantly higher biological activity of the ILZ-hsGITRL compared with hsGITRL was confirmed by CD4+ T proliferation, interferon-γ (IFN-γ) secretion and binding activity assay. To reveal and compare the underlying mechanisms, the level of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation was examined, indicating that ILZ-hsGITRL induced more persistent and stronger ERK1/2 activation than hsGITRL. In conclusion, the incorporation of an ILZ motif could markedly improve the costimulation of hsGITRL.
Monday, July 5, 2010
Mycobacterium tuberculosis promotes HIV trans-infection and suppresses MHC-II antigen processing by dendritic cells
J. Virol. doi:10.1128/JVI.02303-09
Morgan A. Reuter, Nicole D. Pecora, Clifford V. Harding, David H. Canaday, and David McDonald*
Department of Molecular Biology and Microbiology, Department of Pathology, Division of Infectious Diseases, Case/UH Center for AIDS Research, Case Western Reserve University School of Medicine; Geriatric Research, Education and Clinical Center, Louis Stokes VAMC, Cleveland, OH 44106
M. tuberculosis (Mtb) is a leading killer of HIV infected individuals worldwide, particularly in sub-Saharan Africa, where it is responsible for up to 50% of HIV-related deaths. Infection by HIV predisposes individuals to Mtb infection, and co-infection accelerates the progression of both diseases. In contrast to most other opportunistic infections associated with HIV, increased risk of Mtb infection occurs during early stage HIV disease, long before CD4 T cell counts fall below critical levels.
We hypothesized that Mtb infection contributes to HIV pathogenesis by interfering with dendritic cell (DC) mediated immune control.
DCs carry pathogens like Mtb and HIV from sites of infection into lymphoid tissues,where they process and present antigenic peptides to CD4 T cells. Paradoxically, DCs can also deliver infectious HIV to T cells without first becoming infected, a process known as trans-infection.
LPS-activated DCs sequester HIV in pocket-like membrane invaginations that remain open to the cell surface, and individual virions are delivered from the pocket into T cells at the site of contact during trans-infection. Here we report that Mtb exposure increases HIVtrans-infection and induces viral sequestration within surface-accessible compartments identical to those seen in LPS-stimulated DCs.
At the same time, Mtb dramatically decreases the degradative processing and MHC-II presentation of HIV antigens to CD4+ T cells. Our data suggests that Mtb infection promotes a shift in the dynamic balance between antigen processing and intact virion presentation, favoring DC-mediated amplification of HIV infections.
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