CD1b-mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection

doi:10.1084/jem.192.7.965

Published online 2 October 2000.

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© The Rockefeller University Press, 0022-1007/2000/10/965/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 965-976

Original Article

CD1b-mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection

D. Branch Moody^a, Mark R. Guy^b, Ethan Grant^a, Tan-Yun Cheng^a, Michael B. Brenner^a, Gurdyal S. Besra^b, and Steven A. Porcelli^a
^a Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
^b School of Microbiological, Immunological and Virological Sciences, University of Newcastle upon Tyne, The Medical School, NE2 4HH Newcastle upon Tyne, United Kingdom

Correspondence to: D. Branch Moody, Smith Building Rm. 514, 1 Jimmy Fund Way, Boston, MA 02115. Tel:617-525-1037 Fax:617-525-1010

T cells recognize microbial glycolipids presented by CD1 proteins,but there is no information regarding the generation of naturalglycolipid antigens within infected tissues. Therefore, we determinedthe molecular basis of CD1b-restricted T cell recognition ofmycobacterial glycosylated mycolates, including those producedduring tissue infection in vivo. Transfection of the T cellreceptor (TCR) ${alpha}$ and ß chains from a glucose monomycolate(GMM)-specific T cell line reconstituted GMM recognition inTCR-deficient T lymphoblastoma cells. This TCR-mediated responsewas highly specific for natural mycobacterial glucose-6-O-(2R,3R) monomycolate, including the precise structure of the glucosemoiety, the stereochemistry of the mycolate lipid, and the linkagebetween the carbohydrate and the lipid. Mycobacterial productionof antigenic GMM absolutely required a nonmycobacterial sourceof glucose that could be supplied by adding glucose to mediaat concentrations found in mammalian tissues or by infectingtissue in vivo. These results indicate that mycobacteria synthesizedantigenic GMM by coupling mycobacterial mycolates to host-derivedglucose. Specific T cell recognition of an epitope formed byinteraction of host and pathogen biosynthetic pathways providesa mechanism for immune response to those pathogenic mycobacteriathat have productively infected tissues, as distinguished fromubiquitous, but innocuous, environmental mycobacteria.

Key Words: CD1, T cell, antigen presentation, mycobacteria, glucose monomycolate

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