Protection versus pathology in tuberculosis: recent insights

Abstract

Recent studies have revisited the roles of prime players in the immune response to tuberculosis (TB) and have highlighted novel functions of these players. Specifically, immunoregulatory mechanisms mediated by IFNγ have been delineated as well as a novel role for neutrophils in promoting antigen presentation. New insights into the interaction between the bacterium and phagocyte indicate that the bacterium actively promotes phagocyte necrosis rather than apoptosis and that this impacts generation of the acquired response. There are also many new examples of how the phagocyte responds to the bacteria and how it mediates control. The phenotype of protective T cells is also being re-examined. These developments provide promise for improved vaccine design and highlight the complexity of this disease.

Figure

(i) Exposure of lung phagocytes, both mononuclear and granulocytic, to invading Mtb results in the phagocytosis of the bacteria. Virulent Mtb inhibits apoptotic and promotes necrotic cell death of the host phagocyte which delays the transfer of Mtb bacteria and/or Mtb antigens to migratory DCs DLN and thereby slows the initiation of T cell responses.(ii) In the DLN the local expression of antigen and inflammatory cytokines defines the polarization of the T cells which then migrate to the Mtb manipulated inflammatory site. (iii) At this site the immune response is regulated by feedback mechanisms involving IFN and PD-1. (iv) Critical to the development of the immunopathology required for transmission is the strong induction of T cell responses which are then limited in function at the site of infection. T cells fail to penetrate fully the macrophage dominated site and also fail to express full functionality.