Cytotoxicity of CD56(bright) NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A

Article (PDF Available)inPLoS ONE 7(2):e31959 · February 2012with49 Reads
DOI: 10.1371/journal.pone.0031959 · Source: PubMed
In mouse models of chronic inflammatory diseases, Natural Killer (NK) cells can play an immunoregulatory role by eliminating chronically activated leukocytes. Indirect evidence suggests that NK cells may also be immunoregulatory in humans. Two subsets of human NK cells can be phenotypically distinguished as CD16(+)CD56(dim) and CD16(dim/-)CD56(bright). An expansion in the CD56(bright) NK cell subset has been associated with clinical responses to therapy in various autoimmune diseases, suggesting an immunoregulatory role for this subset in vivo. Here we compared the regulation of activated human CD4(+) T cells by CD56(dim) and CD56(bright) autologous NK cells in vitro. Both subsets efficiently killed activated, but not resting, CD4(+) T cells. The activating receptor NKG2D, as well as the integrin LFA-1 and the TRAIL pathway, played important roles in this process. Degranulation by NK cells towards activated CD4(+) T cells was enhanced by IL-2, IL-15, IL-12+IL-18 and IFN-α. Interestingly, IL-7 and IL-21 stimulated degranulation by CD56(bright) NK cells but not by CD56(dim) NK cells. NK cell killing of activated CD4(+) T cells was suppressed by HLA-E on CD4(+) T cells, as blocking the interaction between HLA-E and the inhibitory CD94/NKG2A NK cell receptor enhanced NK cell degranulation. This study provides new insight into CD56(dim) and CD56(bright) NK cell-mediated elimination of activated autologous CD4(+) T cells, which potentially may provide an opportunity for therapeutic treatment of chronic inflammation.
    • "In this regard, there is evidence from mouse and human studies that NK cells exhibit immunoregulatory functions by interacting with controlling populations of different immune cells such as antigen presenting cells, epithelial stromal cells or activated TCD4 + and TCD8 + cells (extensively reviewed by Crome et al. [9] ). Several studies have demonstrated the direct killing of activated T cells mediated by NKG2D [40, 41] or NKp46 activating receptors [23] on NK cells. Poggy et al. [42] showed the killing of autologous antigen presenting and stromal cells only by activated human NK cells that was dependent on LFA1/ CD54 interaction and the activation of NKp30, NKp46 and NKG2D killing receptors. "
    [Show abstract] [Hide abstract] ABSTRACT: PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.
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    • "For example, activated NK cells limit T cell expansion after hematopoietic stem cell transplantation by cytokine-based rather than lytic mechanisms [67][68][69]. Also, NK cell–T cell interactions are often addressed in the context of microbial infections or carcinogenesis, where NK-cell-mediated killing of activated CD4 + or CD8 + T cells is reported and associated with transient T cell acquisition of NK cell targets during the activation process [70, 71]. Reciprocally, CD4 + CD25 + T-regulatory cells suppress NK cell functions [72, 73]. "
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    • "Others have found a NKG2D-mediated killing of T cells by NK cells in mice [38]. In humans, Nielsen and coauthors [26] observed cytotoxicity by CD56 bright NK cells towards activated CD4 þ T cells, mainly mediated by the engagement of NKG2D, LFA-1 and TRAIL. The authors also found that blocking NKp46 decreased degranulation of CD56 bright NK cells in presence of activated CD4 þ T cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Recent evidence has shown that CD56bright NK cells, a subset of NK cells abundant in lymph nodes, may have an immunoregulatory function. In multiple sclerosis (MS), expansion of CD56bright NK cells has been associated to successful response to different treatments and to remission of disease during pregnancy; how whether they exert immunoregulation in physiologic conditions and whether this is impaired in MS is not known. We dissected the immunoregulatory role of CD56bright NK cells function in healthy subjects (HS) and compared it with that of untreated MS subjects or patients with clinically isolated syndrome suggestive of MS (CIS). We found that CD56bright NK cells from HS acquire, upon inflammatory cues, the capability of suppressing autologous CD4+T cell proliferation through direct cytotoxicity requiring engagement of natural cytotoxicity receptors (NCRs) and secretion of granzyme B. CD56bright NK cells from patients with MS/CIS did not differ in frequency and share a similar phenotype but displayed a significantly lower ability to inhibit autologous T cell proliferation. This impairment was not related to deficient expression of NCRs or granzyme B by CD56bright NK cells, but to increased HLA-E expression on T cells from MS/CIS subjects, which could enhance the inhibitory effect mediated by NKG2A that is homogeneously expressed on CD56bright NK cells. The defect in controlling autologous T cells by CD56bright NK cells in MS/CIS might contribute to the excess of autoimmune response that is associated to disease development.
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