The causative agent of
anthrax, Bacillus anthracis, evades the host immune response and establishes
infection through the production of binary
exotoxins composed of Protective
Antigen (PA) and one of two subunits, lethal factor (LF) or
edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define
HLA-DR-restricted and
HLA-DQ-restricted CD4+ T cell responses to the
immunodominant epitopes of PA. This was correlated with the binding affinities of
epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the
Anthrax Vaccine Precipitated (AVP)
vaccine (which contains PA and trace amounts of LF), and patients recovering from
cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse
epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that
HLA-DR1 and
HLA-DQ8 alleles conferred protective immunity relative to
HLA-DR15,
HLA-DR4 and
HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+
T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural
infection and vaccination is vital in planning protective strategies against
anthrax.