NK Cells Regulate CD8+ T Cell Effector Function in Response to an Intracellular Pathogen

Abstract

We studied the role of NK cells in regulating human CD8+ T cell effector function against mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Depletion of NK cells from PBMC of healthy tuberculin reactors reduced the frequency of M. tuberculosis-responsive CD8+IFN-γ+ cells and decreased their capacity to lyse M. tuberculosis-infected monocytes. The frequency of CD8+IFN-γ+cells was restored by soluble factors produced by activated NK cells and was dependent on IFN-γ, IL-15, and IL-18. M. tuberculosis-activated NK cells produced IFN-γ, activated NK cells stimulated infected monocytes to produce IL-15 and IL-18, and production of IL-15 and IL-18 were inhibited by anti-IFN-γ. These findings suggest that NK cells maintain the frequency of M. tuberculosis-responsive CD8+IFN-γ+ T cells by producing IFN-γ, which elicits secretion of IL-15 and IL-18 by monocytes. These monokines in turn favor expansion of Tc1 CD8+ T cells. The capacity of NK cells to prime CD8+ T cells to lyse M. tuberculosis-infected target cells required cell-cell contact between NK cells and infected monocytes and depended on interactions between the CD40 ligand on NK cells and CD40 on infected monocytes. NK cells link the innate and the adaptive immune responses by optimizing the capacity of CD8+ T cells to produce IFN-γ and to lyse infected cells, functions that are critical for protective immunity against M. tuberculosis and other intracellular pathogens.

Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity

“…Either or both of these could be involved in ␤ cell destruction. Indeed, there is increasing evidence that NK cells can ''help'' both CD4 ϩ and CD8 ϩ T cell responses in infectious contexts (34,35). It may be instructive to compare the variations in gene expression profiles observed here with those seen in a kinetic analysis of cyclophosphamideinduced diabetes in BDC2.5͞NOD mice (M. Matos, D.M., and C.B., unpublished work).…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”

“…During Mycobacterium tuberculosis infection in vitro, NK cells control pathogen replication in monocytes via natural cytotoxicity receptor (NCR) killing [21], and removal of NK cells from the peripheral blood of patients with latent tuberculosis significantly reduces mycobacterium-specific CD8 + CTL function [22]. Similarly, the dysfunction of NK cells observed during HIV-1 infection [23,24] has been recently associated with decreased expression of the major NCR (NKp30, NKp46 and NKp44), with a significant level of peripheral NK cell activation and inefficient lysis of HIVinfected CD4 + T cells [25][26][27][28].…”

“…Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33]. In addition, reduced NK cell triggering mediated by reduced expression of NKG2D ligands (MIC-A and MIC-B) on mature DC (mDC) [34] as well as increased NK cell inhibition through increased CD94/NKG2A expression and TGF-b and IL-10 production [35,36,37] have been suggested to occur during HCV infection.Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”

Discordant responses to HAART in HIV-1 patients: the need to focus on intervention

“…In addition, patients with IDR have low CD4 + T-cell numbers with a hyperactivated/apoptotic phenotype and an increased size of the HIV reservoir as a possible expression of incomplete virus control, while their thymic function is reduced only partially [14]. Therefore, based on these findings, it remains to be evaluated whether HIV-associated alterations in innate immunity with derangement of natural killer (NK) cell phenotype and function in IDR patients [15][16][17] are involved in altered monocyte and dendritic cell editing [18][19][20] with impaired recovery of CD4 + cell numbers and function. In this case, potential interventions specifically addressing innate immunity [21] could contribute to improve the response to HAART.…”