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Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all [HLA-B*57:01.sup.+] patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse [CD8.sup.+] T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced [CD8.sup.+] T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of [CD4.sup.+] T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive [CD8.sup.+] T cells with an effector-like and skin-homing phenotype along with [CD8.sup.+] infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented [CD8.sup.+] T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive [CD8.sup.+] T cells dependent on both HLA genetic risk and immunoregulatory host factors., Introduction Adverse drug reactions (ADRs) have been defined by the World Health Organization (WHO) as noxious and unintended responses to a drug given at a dose established for the prophylaxis, [...]

Previous studies revealed the existence of foreign antigen-specific memory phenotype CD8 T cells in unimmunized mice. Considerable evidence suggests this population, termed "virtual memory" (VM) CD8 T cells, arise via physiological homeostatic mechanisms. However, the antigen-specific function of VM cells is poorly characterized, and hence their potential contribution to immune responses against pathogens is unclear. Here we show that naturally occurring, polyclonal VM cells have unique functional properties, distinct from either naïve or antigen-primed memory CD8 T cells. In striking contrast to conventional memory cells, VM cells showed poor T cell receptor-induced IFN-γ synthesis and preferentially differentiated into central memory phenotype cells after priming. Importantly, VM cells showed efficient control of Listeria monocytogenes infection, indicating memory-like capacity to eliminate certain pathogens. These data suggest naturally arising VM cells display unique functional traits, allowing them to form a bridge between the innate and adaptive phase of a response to pathogens. [ABSTRACT FROM AUTHOR]