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.

Figure 1. Model of the mechanism of tolerance or hypersensitivity to abacavir in HLA-B*57:01–Tg mice.

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 CD44^hiCD62L^hiCD8⁺ Tcm cells (see inset). CD4⁺ T cell depletion results in the maturation of DCs to a CD86^hiCD80^hiPD-L1^hi 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 (CD86^loCD80^loPD-L1^lo), and the mouse remains tolerant to the altered peptide repertoire. Tcm, T central memory cell; TCR, T cell receptor.