T cells in mycobacterial infection and disease

Abstract

There has been an increase in our understanding of the complexity of the T cell response to mycobacterial infection recently. Improved tools have allowed the determination of the location and kinetics of naïve T cell activation in the mouse as well the variety of function of mycobacteria-specific cells in humans. There is also an increased appreciation of the balance required during mycobacterial infection between anti-bacterial activity and control of the immunopathologic response. The integration of the T cell functional data with the consequences of infection should improve rational vaccine design.

Figure 1. The importance of location and functionality of both antigen-specific lymphocytes and infected phagocytes in rapid vaccine-induced control of Mtb

In order for vaccine-induced memory T cells to be effective against pulmonary challenge with Mtb they must be in the correct location i.e. in the lung close to where phagocytes first become infected. In addition, the infected phagocyte must be expressing signals (i.e. mycobacterial antigen in class I or class II) in order to activate the memory effector cells to locally express their effector function. The infected phagocyte within the lung must also be able to be responsive to the signals (both IFNγ dependent and independent) in order for mycobacterial growth to come under rapid control. While CD4 T cells mediate primary control of Mtb in infection, CD8 T cells can be activated by vaccination and mediate protection.

Figure 2. Regulation of the protective response to Mtb occurs on several levels

Infection with Mtb results in accumulation of mononuclear phagocytes and lymphocytes in the lung; granulocytes are associated with detrimental inflammation. These cellular accumulations occur within the normal interstitium of the lung and interfere with lung function. Regulating inflammation and tissue damage is essential to maintaining the critical function of the lung. Cytokines (IL-10, TGFβ) provide control of phagocyte activation, while IFNγ and TNFα provide feedback loops that induce regulatory T cells, limit effector T cell survival and limit production of proinflammatory molecules. Regulatory T cells expand with effector cells and infiltrate the inflammation and likely limit effector cell function. Regulators of intracellular signaling (TIR8, DAP12) as well as decoy and inhibitory receptors (DR6, FcγRIIB) curtail immunopathologic consequences during Mtb infection.