Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration
Elizabeth J. Phillips, Simon A. Mallal
Elizabeth J. Phillips, Simon A. Mallal
Published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2746-2749. https://doi.org/10.1172/JCI121525.
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Commentary

Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Abstract

The discovery of HLA-B*57:01–associated abacavir hypersensitivity is a translational success story that eliminated adverse reactions to abacavir through pretreatment screening and defined a mechanistic model of an altered peptide repertoire. In this issue of the JCI, Cardone et al. have developed an HLA-B*57:01–transgenic mouse model and demonstrated that CD4+ T cells play a key role in mediating tolerance to the dramatically altered endogenous peptide repertoire induced by abacavir and postulate a known mechanism by which CD4+ T cells suppress DC maturation. This report potentially explains why 45% of HLA-B*57:01 carriers tolerate abacavir and provides a framework for future studies of HLA-restricted, T cell–mediated drug tolerance and hypersensitivity.

Authors

Elizabeth J. Phillips, Simon A. Mallal

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Figure 1

Model of the mechanism of tolerance or hypersensitivity to abacavir in HLA-B*57:01–Tg mice.

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Model of the mechanism of tolerance or hypersensitivity to abacavir in H...
Model of the mechanism of tolerance or hypersensitivity to abacavir in HLA-B*57:01–Tg mice. Abacavir binds noncovalently to residues on the floor of the peptide-binding groove of the HLA-B*57:01 molecule and the overlying endogenous peptide, dramatically altering the repertoire of endogenous peptides presented to early-responding CD44hiCD62LhiCD8+ Tcm cells (see inset). CD4+ T cell depletion results in the maturation of DCs to a CD86hiCD80hiPD-L1hi phenotype that is capable of costimulation and induction of effector CD8+ T cells that can home to the skin and induce hypersensitivity. Without CD4+ T cell depletion, DCs remain in an immature state (CD86loCD80loPD-L1lo), and the mouse remains tolerant to the altered peptide repertoire. Tcm, T central memory cell; TCR, T cell receptor.