Regulation of Immunity to Tuberculosis

Regulatory T cell suppression of antigen-presenting cells (APCs). CTLA-4 on the surface of Treg cells can prevent or depress the upregulation of CD80 and CD86, the major costimulatory molecules on APC. LAG-3 on Treg cells can interact with MHC class II on APCs, by binding of LAG-3 to MHC class II molecules on immature DCs, causing an inhibitory signal that suppresses DC maturation and immaturity. Tissue destruction results in extracellular ATP that functions as an indicator and exerts inflammatory effects on DCs. Catalytic inactivation of extracellular ATP by CD39 represents an anti-inflammatory mechanism that may be used by Treg cells to prevent the deleterious effects of ATP on antigen-presenting cell function. In contrast, Nrp-1 (neuropilin) promotes extended interactions between Treg cells and immature DCs and limits access of the effector cells to APCs.

A combination of host immune factors and M. tuberculosis strain virulence can result in a distinctive host immunophenotype over time, resulting in multiple outcomes. During infection too little Treg activity can lead to a greater Th1 immune response, resulting in tissue damage and bacterial growth. A balance of both Th1 and Treg immunity can result in proper antibacterial immunity, leading to reduced TB growth. Excessive Treg activity results in a counterregulatory Treg response that ultimately impairs host immunity against the tubercle bacillus, allowing disease progression.

Model of proposed regulatory T cell suppression in mice BCG vaccinated and exposed to clinical M. tuberculosis and clinical M. tuberculosis alone. (Top) The initial BCG vaccination results in bacterial lymph node persistence in the animal TB model that leads to the presence of Treg and Th17 cells. Upon a subsequent infection with M. tuberculosis Th1 and Th17 cells expand at a high rate, causing GR1+ influx and pulmonary tissue damage. In an attempt to limit this damage Tregs expand with Th1 immunity and produce IL-10 and CTLA4 binds to CD80/CD86 costimulatory molecules to limit effector T cell expansion. The abundance of Th17 cells can also have a negative regulatory feedback on Th1 effector cells. (Bottom) M. tuberculosis infection in mice results in expansion of Th1 IFN-γ effector cells capable of limiting further expansion of Th17 cells producing IL-17 induction of GR1+ cells and pulmonary pathology. Treg cells will expand with the Th1 effector immunity limiting Th17 cells through IL-2 consumption with CD25 or IL-10 production.