This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Mahon, R. N.
Right arrow Articles by Boom, W. H.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mahon, R. N.
Right arrow Articles by Boom, W. H.

 Previous Article  |  Next Article 

Infection and Immunity, October 2009, p. 4574-4583, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00222-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mycobacterium tuberculosis Cell Wall Glycolipids Directly Inhibit CD4+ T-Cell Activation by Interfering with Proximal T-Cell-Receptor Signaling{triangledown}

Robert N. Mahon,1* Roxana E. Rojas,2 Scott A. Fulton,2 Jennifer L. Franko,1,2 Clifford V. Harding,1,{dagger} and W. Henry Boom1,2,3,{dagger}

Department of Pathology, Case Western Reserve University and University Hospitals, Case Medical Center, Cleveland, Ohio 44106,1 Department of Medicine, Case Western Reserve University and University Hospitals, Case Medical Center, Cleveland, Ohio 44106,2 Tuberculosis Research Unit, Case Western Reserve University and University Hospitals, Case Medical Center, Cleveland, Ohio 441063

Received 25 February 2009/ Returned for modification 14 May 2009/ Accepted 29 July 2009

Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust adaptive CD4+ T-cell responses. We have previously shown that M. tuberculosis can indirectly inhibit CD4+ T cells by suppressing the major histocompatibility complex class II antigen-presenting cell function of macrophages. This study was undertaken to determine if M. tuberculosis could directly inhibit CD4+ T-cell activation. Murine CD4+ T cells were purified from spleens by negative immunoaffinity selection followed by flow sorting. Purified CD4+ T cells were activated for 16 to 48 h with CD3 and CD28 monoclonal antibodies in the presence or absence of M. tuberculosis and its subcellular fractions. CD4+ T-cell activation was measured by interleukin 2 production, proliferation, and expression of activation markers, all of which were decreased in the presence of M. tuberculosis. Fractionation identified that M. tuberculosis cell wall glycolipids, specifically, phosphatidylinositol mannoside and mannose-capped lipoarabinomannan, were potent inhibitors. Glycolipid-mediated inhibition was not dependent on Toll-like receptor signaling and could be bypassed through stimulation with phorbol 12-myristate 13-acetate and ionomycin. ZAP-70 phosphorylation was decreased in the presence of M. tuberculosis glycolipids, indicating that M. tuberculosis glycolipids directly inhibited CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University and University Hospitals, Case Medical Center, 10900 Euclid Avenue, BRB 1010B, Cleveland, OH 44106-4984. Phone: (216) 368-4855. Fax: (216) 368-2034. E-mail: rnm4{at}case.edu

{triangledown} Published ahead of print on 3 August 2009.

Editor: J. L. Flynn

{dagger} W. Henry Boom and Clifford V. Harding share senior authorship.

Infection and Immunity, October 2009, p. 4574-4583, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00222-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»