Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells

Abstract

It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis, but that only 10% of infected people break down with the disease. In the remaining 90% the infection remains clinically latent. In the present study, the immune mechanisms controlling the latent phase of tuberculosis infection were evaluated in a mouse model of latency and reactivation. Mice aerosol-infected with M. tuberculosis were treated with anti-mycobacterial drugs resulting in very low, stable bacterial numbers (<500 CFU in the spleen and lung) for 10-12 weeks followed by reactivation of the disease with increasing bacterial numbers. During latency, pathological changes in the lung had almost completely resolved and lymphocyte number and turnover were at the pre-infection level. The CD4 subset was highly active during the acute phase of infection and could be detected by intracellular staining for IFN-gamma as well as after antigen-specific stimulation with mycobacterial antigens. The CD8 subset was not involved in the acute stage of infection, but this subset was active and produced IFN-gamma during the latent phase of infection. In vivo depletion of T cell subsets supported these findings with a 6-7-fold increase in bacterial numbers in the lung following anti-CD4 treatment during the acute phase, while anti-CD8 treatment did not have an effect. The opposite was found during the latent phase where anti-CD8 treatment as well as anti-IFN-gamma treatment both resulted in a 10-fold increase in bacterial numbers in the lung, while anti-CD4 treatment induced only a modest change.

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

“…The fact that mice devoid of CD8 + T cells still succumb to Mtb infection despite the development of fully functional CD4 + T cell responses, corroborates results from other investigators showing that CD8 + T cells play an important role in controlling latent and chronic infection [11,35]. Maintenance of CD8 + T cells is critically dependent upon the two common c chain cytokines IL-7 and IL-15.…”

“…However, NK cells have previously been shown to have no impact on early resistance to Mtb infection [46], and the lack of an early effect on mycobacterial proliferation or survival in IL-15-knockout mice is compatible with this notion. In contrast, CD8 + T cells have been implicated in protective immune responses during the chronic phase of TB [4,5,11]. Because survival kinetics of Mtb-infected IL-15 -/-mice were comparable to the outcome of infection in mice lacking MHC class I or perforin [3,4,47], our results support the interpretation that IL-15 may selectively promote CD8 + T cell-mediated protection during TB.…”

“…CD8 + T cells can also cause death of both target cells and their intracellular bacterial cargo, either through perforin-dependent cytolysis by the release of granzymes and granulysin, or by ligation of Fas ligand (FasL) on their surface with Fas on infected macrophages [5,[8][9][10]. Because CD8 + T cells are involved in protection during the chronic stage of TB [4,5,11], and participate in memory immune responses to Mtb infection [12], generating a more robust CD8 + T cell response may provide an effective vaccination strategy to the control and clearance of infection. Thus, exploring the mechanisms which exclusively promote the expansion of activated effector and memory CD8 + T cells may improve vaccine-induced immune protection against TB.…”

“…Because CD8 + T cells are involved in protection during the chronic stage of TB [4,5,11], and participate in memory immune responses to Mtb infection [12], generating a more robust CD8 + T cell response may provide an effective vaccination strategy to the control and clearance of infection. Thus, exploring the mechanisms which exclusively promote the expansion of activated effector and memory CD8 + T cells may improve vaccine-induced immune protection against TB.…”

Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

“…Double gene DNA vaccine against tuberculosis S-J Ha et al stage of infection, but CD8 + T cells are critical in the control of latent infection. 29 Thus, both CD4 + and CD8 + T-cell responses induced by our double-gene DNA vaccine can lead to an efficient control of bacterial growth during both stages of infection.…”