Figure 9. Model of TcpB disruption of adaptive immune response during brucellosis. T.

 =  TcpB; BCV  =  Brucella containing vacuole; ER  =  endoplasmic reticulum. TcpB can inhibit CD8+ T cell specific killing of B. melitensis specific target cells. We hypothesize that this inhibition results from the binding of TcpB to PI(4,5)P₂ and either blocking its action or sequestering it away from the APC side of the immunological synapse. Also, TcpB contains a membrane translocation domain that may allow it to travel into the responding CD8+ T cell. We hypothesize that TcpB binding of PI(4,5)P₂ and PI(3,4,5)P₃, TcpB is disrupting by either up-regulating or down-regulating the action of FoxO and/or mTOR. We hypothesize that this disruption leads to decreased numbers of CD8+ T cell making the effector to memory transition necessary for protective immunity. IL-2 and IL-12 activate PI3K which phosphorylates PI(4,5)P₂ into PI(3,4,5)P₃. This triggers activation of PKB by PDK1, which can then phosphorylate FoxO and lead to its degradation, and PKB can activate mTOR complex 1. mTORC1 can then up-regulate T-bet, down-regulate Eomes, activate Klf2, and possibly activate FoxO. These actions regulate the fate (short-lived effector or long-lived memory) of the responding CD8+ T cell. Rapamycin and metformin target mTOR and AMPK respectively leading to modulation of memory cell development. Adapted from [17].