CBA / J mice generate protective immunity to soluble A g85 but fail to respond efficiently to A g85 during natural M ycobacterium tuberculosis infection

In CBA/J mice, susceptibility to M ycobacterium tuberculosis ( M .tb ) is associated with low interferon‐gamma ( IFN ‐γ) responses to antigens ( A ntigen 85 ( A g85) and early secreted antigenic target‐6 (ESAT‐6)) that have been defined as immunodominant. Here, we asked whether the failure of CBA/J mice to recognize A g85 is a consequence of M .tb infection or whether CBA/J mice have a general defect in generating specific T ‐cell responses to this protein antigen. We compared CBA/J mice during primary M .tb infection, A g85 vaccination followed by M .tb challenge, or M .tb memory immune mice for their capacity to generate A g85‐specific IFN ‐γ responses and to control M .tb infection. CBA/J mice did not respond efficiently to A g85 in the context of natural infection or re‐infection. In contrast, CBA/J mice could generate A g85‐specific IFN ‐γ responses and protective immunity when this antigen was delivered as a soluble protein. Our data indicate that although M .tb infection of CBA/J mice does not drive an A g85 response, these mice can fully and protectively respond to A g85 if it is delivered as a vaccine. The data from this experimental model suggest that the A g85‐containing vaccines in clinical trials should protect M .tb susceptible humans.