CD8 T Cells in Old Mice Contribute to the Innate Immune Response toMycobacterium tuberculosisvia Interleukin-12p70-Dependent and Antigen-Independent Production of Gamma Interferon

Abstract

Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8-and gamma interferon (IFN-␥)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-␥ expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-␥ production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-␥ levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-␥. Additional characterizations of the signaling events that lead to enhanced innate IFN-␥ production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.

The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells

“…19 In support of our earlier study, Vesosky et al have identified the SET-PP2A interplay as being one possible mechanism by which CD8 T cells from aged mice produce enhanced levels of IFN-␥ in response to Mycobacterium tuberculosis after IL-12 and IL-18 stimulation. 27 In the current study, we hypothesized that SET could regulate NK cell-mediated cytotoxic activity via its regulation of PP2A. Performing loss-or gain-of-function experiments, we confirmed our preliminary evidence that modulation of SET altered cytotoxic activity of the NK-92 cell line.…”

Fingolimod targeting protein phosphatase 2A differently affects IL‐33 induced IL‐2 and IFN‐γ production in CD8+ lymphocytes

“…IFN-γ mRNA expression was associated with increased SET mRNA expression. Along these lines IL-18/IL-12 induced IFN-γ production by murine CD8 + was inhibited by forskolin, a known PP2A activator, which also decreased p-STAT4 levels [49]. Since FTY720 and not FTY720-P is known to bind a hydrophobic pocket of SET that leads to SET inactivation and PP2A activation, our data indicate that FTY720 inhibits IFN-γ via this pathway.…”

“…Downstream of SET, active PP2A may then dephosphorylate and inhibit IFN‐ γ related transcription factors, e.g. IFN‐ γ related pSTAT1 and pSTAT4 . Ntranos et al.…”

Autophagic Killing Effects against Mycobacterium tuberculosis by Alveolar Macrophages from Young and Aged Rhesus Macaques

“…Despite the failure of old mice to control M. tuberculosis infection, subsequent work demonstrated that upon low-dose infection, old mice possessed a transient early resistance to M. tuberculosis that was mediated by CD8+ T cells [39], [40]. Turner has therefore proposed a model whereby old mice are able to mount an early innate response, but delayed generation of an adaptive immune response results in higher bacterial burden and inflammation [41]. Further investigation into the mechanisms of effective immune control of M. tuberculosis and application of this knowledge to the benefit of the elderly population is necessary.…”