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

Abstract

CD8 + T cells are involved in protection againstMycobacterium tuberculosis infection and represent a promising target for new vaccine strategies. Because IL-15 is important for the homeostasis of CD8 + T cells, we studied the immune response in IL-15-deficient mice during tuberculosis. In the absence of IL-15, CD8 + T cells failed to efficiently accumulate in draining lymph nodes and at the site of infection. The expression of antigen-specific effector functions, such as the production of interferon-c and cytotoxicity, were impaired in CD8 + T cells, but not CD4 + T cells, from IL-15-deficient mice. This defect was associated with an increased mortality of IL-15-deficient mice during the chronic phase of infection. The lectin-like stimulatory receptor natural killer group 2D (NKG2D) was up-regulated on CD8 + T cells only from wild-type mice, but not from IL-15-deficient mice. Mechanistically, blocking NKG2D function with an mAb inhibited M. tuberculosis-directed CD8 + T cell responses in vitro. We conclude that in addition to regulating the expansion of CD8 + T cells, IL-15 is also necessary for inducing effector mechanisms in CD8 + T cells that depend on NKG2D expression. Hence, our results implicate IL-15 and NKG2D as promising targets for modulating CD8 + T cellmediated protection against tuberculosis. IntroductionHuman tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is responsible for eight million new cases and two million deaths annually [1]. Improved vaccination strategies will need to target all mechanisms that contribute to restricting the growth of Mtb [2]. Although the cell-mediated immune response is known to be critical in host defense against infection with mycobacteria, the relative contribution of T cell subsets and the mechanisms by which T cells participate in the control of infection are still not completely defined. It is generally accepted that both, CD4 + and CD8 + T cells, are an essential component of protective immunity against TB [3]. CD4 + T cells are particularly critical during the early phase of infection, while CD8 + T cells appear to contribute mostly at later stages [4,5]. Both, CD4 + and CD8 + T cells, produce interferon-c (IFN-c) which in turn stimulates the anti-microbial activity of macrophages. Intracellular pathogens are then killed through reactive nitrogen intermediates produced by the inducible nitric oxide synthase [6] or through effector mechanisms mediated by the newly described member of the 47-kD guanosine triphosphatase family, . 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 strate...

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8+T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

“…The proliferation of antigen-specific CD8 ϩ T cells was not affected following anti-NKG2D treatment, because there were no differences in the total numbers of T cells or virusspecific CD8 ϩ T cells within the CNS following viral infection. Other reports indicate that blocking NKG2D on mouse CTLs negatively affects numerous effector functions, including proliferation, the production of IFN-␥, and lytic activity (41,60,64,74). There are several possible explanations for the results obtained from our experiments.…”

“…Previous studies have shown that blocking NKG2D receptor signaling diminishes IFN-␥ secretion by T cells (9,69,74). Given that IFN-␥ is important in the control of JHMV replication within the CNS and in host survival, it is plausible that anti-NKG2D treatment of JHMV-infected mice affects IFN-␥ secretion by infiltrating T cells (69).…”

“…Treatment of lymphocytic choriomeningitis virus-specific CD8 ϩ T cells with an NKG2D-activating antibody augmented proliferation compared to that of cells treated with control antibody, indicating that NKG2D receptor signaling on CD8 ϩ T cells offers protection against virus-induced disease (41). Ex vivo anti-NKG2D treatment of Mycobacterium tuberculosis antigenspecific CD8 ϩ T cells resulted in decreased IFN-␥ secretion and CTL activity when cultured with bacterial peptide-stimulated macrophages compared to treatment with an isotypematched control antibody, suggesting that NKG2D receptor signaling on CD8 ϩ T cells affects the outcome of disease (74). Finally, blocking NKG2D receptor signaling in mice persistently infected with JHMV results in diminished immune-mediated pathology, suggesting that IFN-␥ production from ␥␦ T cells is impaired (18).…”

“…NKG2D is a type II transmembrane glycoprotein that is expressed as a disulfide-linked homodimer on the surface of NK cells, CD8 ϩ T cells, and ␥␦ T cells in mice (20,41). In some situations, NKG2D functions as a costimulatory receptor for CD8 ϩ T cells following an encounter with cells expressing NKG2D ligands, resulting in enhanced effector functions and cell proliferation (35,41,60,64,74). For example, antiviral effector responses by some human cytomegalovirus antigen-specific CD8 ϩ T clones characterized by cytokine bursts are amplified when cultured with viral peptide-pulsed cells expressing the human NKG2D ligand MICA (35).…”

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

“…IL-15 has been reported to participate in protection against M.tb infection [43]. This process could contribute to the high resistance to H37Ra even in the absence of iNOS.…”