CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

Abstract

The contribution of CD8؉ T cells to the control of tuberculosis has been studied primarily during acute infection in mouse models. Memory or recall responses in tuberculosis are less well characterized, particularly with respect to the CD8 T-cell subset. In fact, there are published reports that CD8 ؉ T cells do not participate in the memory immune response to Mycobacterium tuberculosis. We examined the CD8 ؉ T-cell memory and local recall response to M. tuberculosis. To establish a memory immunity model, C57BL/6 mice were infected with M. tuberculosis, followed by treatment with anti-mycobacterial drugs and prolonged rest. ؉ and CD8 ؉ T cells in the lungs of immune mice expressed the activation marker CD69 and could be restimulated to produce gamma interferon (IFN-␥). In contrast, <6% of T cells in the lungs of naive challenged mice were CD69؉ at 1 week postchallenge, and IFN-␥ production was not observed at this time point. CD8؉ T cells from the lungs of both naive and memory mice after challenge were cytotoxic toward M. tuberculosis-infected macrophages. Our data indicate that memory and recall immunity to M. tuberculosis is comprised of both CD4؉ and CD8 ؉ T lymphocytes and that there is a rapid response of both subsets in the lungs following challenge. Control of acute tuberculosis in mice involves participation of CD8ϩ T cells (6,22,37), although a recent publication argues for a more important role for this subset in control of persistent infection (38). Recent studies on the development and activation of mycobacterium-specific CD8 ϩ T cells have indicated that substantial numbers of activated CD8 ϩ T lymphocytes with both cytokine-secreting and cytotoxic functions are present in the lungs during the acute phase of infection in mice (13,19,(33)(34)(35). However, whether this acute response culminates in the development of memory CD8 ϩ T-cell populations that can respond robustly to a secondary Mycobacterium tuberculosis challenge is not clear. It is believed that a proper memory response develops after an infection is cleared. CD8 ϩ T cells play a prominent role during memory immune responses in intracellular bacterial infections with Listeria monocytogenes (11) and Chlamydia pneumoniae (31). In the mouse model and in humans, M. tuberculosis can be a persistent or latent infection. To study the memory response in this infection, it is useful to first reduce or eliminate the bacterial burden in the mouse tissues. It has been reported that the treatment of infected mice with antibiotics leads to the development of an immune response capable of reducing the bacterial burden after challenge (4). The major role in combating bacterial challenge during memory immune responses so far has been attributed exclusively to CD4 ϩ T cells (4). Earlier studies have argued against the participation of memory CD8 ϩ T cells in the recall immune responses in a murine model of tuberculosis (3,4,30). However, the development of a memory CD8 ϩ T-cell population during M. tuberculosis infection is supported by the findings that ...

Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02ACandidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults

“…CD40 ligand has been identified as a marker for activated antigen-specific T cells; it is a costimulatory ligand needed to provide T-cell help (7,13,38). A role for CD8 ϩ T cells in the protection against TB has been demonstrated (15,23,27,32). Similar to results from an earlier study with Mtb72F/AS02 A (42) and studies with the MVA85a TB vaccine candidate (5,18,31), no vaccine-induced antigen-specific CD8 ϩ T cells could be detected by ICS using a short-term in vitro restimulation.…”

Impaired Protection against Mycobacterium bovis Bacillus Calmette-Guérin Infection in IL-15-Deficient Mice

“…In contrast, the resistance to M. tuberculosis infection in both perforin-and Fas-deficient mice was unaltered, suggesting that the cytotoxic function of CD8 ϩ T cells may not be critical in protection against tuberculosis (11). A recent study has suggested that CD8 ϩ T cells are more important than CD4 ϩ T cells in controlling the latent phase of tuberculosis infection, which comprises the majority of human infections (12)(13)(14). Thus, it appears that protection against chronic pulmonary tuberculosis requires a sustained cellular immunity mediated by CD8 ϩ T cells and that Ag-specific CD8 ϩ T cells are a major target for vaccine design.…”

“…Ag-specific CD8 ϩ T cells are an important T cell subset for controlling the late phase of tuberculosis infection (13,14). Unfortunately, immunostimulatory BCG-derived peptides recognized by CD8 ϩ T cells have not been defined.…”

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

“…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.…”

“…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.…”