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J. Exp. Med.,
Volume 189, Number 2, January 18, 1999 265-278
By
From the * Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Sydney, New South
Wales 2042, Australia; and the The mechanism of self-tolerance in the CD4+ T cell compartment was examined in a double
transgenic (Tg) model in which T cell receptor (TCR)- Department of Microbiology and Immunology and The Howard
Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5402
/
Tg mice with specificity for the
COOH-terminal peptide of moth cytochrome c in association with I-Ek were crossed with
antigen Tg mice. Partial deletion of cytochrome-reactive T cells in the thymus allowed some
self-specific CD4+ T cells to be selected into the peripheral T cell pool. Upon restimulation
with peptide in vitro, these cells upregulated interleukin (IL)-2 receptor but showed substantially lower cytokine production and proliferation than cells from TCR Tg controls. Proliferation and cytokine production were restored to control levels by addition of saturating concentrations of IL-2, consistent with the original in vitro definition of T cell anergy. However, the
response of double Tg cells to superantigen stimulation in the absence of exogenous IL-2 was
indistinguishable from that of TCR Tg controls, indicating that these self-reactive cells were
not intrinsically hyporesponsive. Measurement of surface expression of Tg-encoded TCR and chains revealed that cells from double Tg mice expressed the same amount of TCR- as
cells from TCR Tg controls, but only 50% of TCR-, implying expression of more than one
chain. Naive CD4+ T cells expressing both Tg-encoded and endogenous chains also manifested an anergic phenotype upon primary stimulation with cytochrome c in vitro, suggesting
that low avidity for antigen can produce an anergic phenotype in naive cells. The carboxyfluorescein diacetate succinimidyl ester cell division profiles in response to titered peptide ± IL-2 indicated that expression of IL-2 receptor correlated with peptide concentration but not
TCR level, whereas IL-2 production was profoundly affected by the twofold decrease in specific TCR expression. Addition of exogenous IL-2 recruited double Tg cells into division, resulting in a pattern of cell division indistinguishable from that of controls. Thus, in this experimental model, cells expressing more than one chain escaped negative selection to a soluble
self-protein in the thymus and had an anergic phenotype indistinguishable from that of low
avidity naive cells. The data are consistent with the notion that avidity-mediated selection for
self-reactivity in the thymus may lead to the appearance of anergy within the peripheral, self-reactive T cell repertoire, without invoking the induction of hyporesponsiveness to TCR-mediated signals.
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