AIDSWEEKLY Plus; Monday, December 7, 1998
Daniel J. DeNoon, Senior Editor
Science is now on the verge of a major breakthrough in understanding the regulation of cellular immunity. Ligands capable of partially activating T cells - known as altered peptide ligands (APL), TCR partial agonists, or TCR antagonists - have for the first time been demonstrated in vivo.
Whether such ligands play a major or minor role in cellular immunity remains to be seen, but the new findings move this field of inquiry out of culture dishes and into animal models.
"These results unequivocally demonstrate in vivo antagonism by an endogenous APL and characterize a class of self-peptides that, although inefficient in causing deletion in the thymus, effectively modulate T-cell responses in the periphery," wrote Devraj Basu, Calvin B. Williams, and Paul M. Allen of Washington University, St. Louis, Missouri.
Basu et al. reported their findings in the Proceedings of the National Academy of Sciences ("In Vivo Antagonism of A T-Cell Response by An Endogenously Expressed Ligand," PNAS, 1998;95:14332-6).
It once was thought that any ligand capable of occupying a TCR fully activated the cell that expressed it. But numerous studies have shown, at least in vitro, that a number of variant T-cell epitopes are capable of down-regulating T-cell responses.
At first this phenomenon was described for mutant epitopes produced by pathogens: HIV, hepatitis B virus, and strains of the malaria pathogen Plasmodium falciparum. In these cases, the TCR antagonists apparently help the pathogens to evade immune surveillance.
But partial activation of T cells may not always be detrimental. A recent study by the Allen team discovered that a peptide derived from mouse hemoglobin acts as an APL (Vidal, K. et al., J Exp Med, 1996;183:1311-21). Such endogenous APLs could modulate primary T-cell responses and affect thymic development of T cells.
In a commentary article, University of Minnesota researcher Stephen C. Jameson noted that APL can induce development of CD8(+) cytotoxic T cells in the thymus, and that APL may be able to deliver signals to immature T cells that mature T cells ignore.
"These findings imply that at least some ligands which induce T- cell development may be capable of regulating the mature T-cell response - an interesting solution for an immune system obsessed with checks and balances," Jameson wrote ("T Cell Receptor Antagonism In Vivo, At Last," PNAS, 1998;95:14001-2).
Basu et al. believe this to be the case.
"Our results contribute to the rapidly emerging concept of endogenous TCR ligands as essential modulators of T-cell function," they wrote. "The ultimate importance of our observations here will be dictated by the percentage of the T-cell repertoire that exists under the influence of such endogenous antagonists. ... Whether endogenous antagonists influence a small subset of T cells or are broad sculpting forces that carve out the landscapes of all T-cell responses remains to be seen."
This work was supported by grants from the National Institutes of Health and the American Cancer Society.
The corresponding author for this study is Paul M. Allen,
Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, St. Louis, Missouri 63110. Email: <allen@immunology.wustl.edu>.
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