The Rapid Induction of HLA-E Is Essential for the Survival of Antigen-Activated Naive CD4 T Cells from Attack by NK Cells
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. The Journal of Immunology
(Impact Factor: 4.92).
10/2010; 185(10):6031-40. DOI: 10.4049/jimmunol.1000176
Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-α-matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-α-matured DCs. An Ab blockade revealed a critical role for the HLA-E-NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation.
Available from: Birgitte Ursø
- "Interestingly, resting DCs and microglia are susceptible to NK cell-mediated cytotoxicity , , whereas activation of these cells upregulates MHC class I molecules and confers resistance to lysis . On the contrary, resting monocytes, monocyte-derived macrophages and T cells are protected from NK cell-mediated cytotoxicity, but upon activation these cells upregulate NKG2D ligands and become susceptible to NK cell lysis , , , , . We found that resting CD4+ T cells expressed much lower levels of all MHC class I molecules compared to activated CD4+ T cells (Fig. S3), yet resting CD4+ T cells were not susceptible to NK cell-mediated lysis, and blocking with an anti-HLA class I antibody did not result in NK cell degranulation. "
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ABSTRACT: 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.
PLoS ONE 02/2012; 7(2):e31959. DOI:10.1371/journal.pone.0031959 · 3.23 Impact Factor
Available from: Koichiro Usuku
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ABSTRACT: Author Summary
Hepatitis C virus (HCV) and human T-cell leukemia virus (HTLV-I) infect millions of people worldwide. Some HCV-infected individuals spontaneously clear the virus and many HTLV-1-infected people remain asymptomatic; however, in both cases the infection can lead to serious illness such as cancer. The factors which determine outcome are still elusive. We have found that a gene that encodes a receptor (KIR2DL2) enhances both protective and detrimental HLA class I-mediated immunity to HCV and HTLV-1. Strikingly, although KIRs are primarily associated with innate immunity, our observations suggest that they also have a major impact on the efficiency of the adaptive immune response. This work helps to explain why one individual infected with a virus remains healthy but another, infected with the same virus develops disease; it also helps to explain why particular HLA class I molecules do not always protect or cause susceptibility as expected. Interestingly, the impact of the KIR is entirely context dependent: if an HLA class I molecule is protective then protection is enhanced, but in the context of a detrimental HLA then susceptibility is enhanced. This study reveals a novel role for inhibitory KIRs in adaptive immunity.
PLoS Pathogens 10/2011; 7(10):e1002270. DOI:10.1371/journal.ppat.1002270 · 7.56 Impact Factor
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ABSTRACT: Natural killer (NK) cells are key members of innate immunity against tumor and infection. Killer cell immunoglobulin-like receptor (KIR) genes regulates NK cell function, which varies substantially between individuals in the number and type. Specific KIRs are associated with certain diseases. Herein we investigated if KIR genes are associated with thyroid cancer risk. Eighty-five patients with thyroid cancer were characterized for the presence and absence of 11 variable KIR genes using a gene-specific PCR typing system, and compared with our recently published healthy control data. Overall, a trend toward more activating KIR receptors was observed in thyroid cancer patients compared to the healthy controls. Particularly, the activating KIR2DS5 gene was significantly increased in patients compared to the controls. Additionally, three other genes (3DS1-2DL5-2DS1) that are strongly linked to KIR2DS5 at the telomeric region of the KIR gene complex [called Telomeric 4 (T4) gene cluster] were also more predominant in the thyroid cancer patient group than in healthy controls. A similar trend of having more of the T4 gene cluster was also reported in a previous study with cervical neoplasia. Together, these data suggest that specific activating KIR genes in cancer patients could generate a chronic inflammatory condition resulting in a tumor microenvironment that may favor tumor growth.
Human immunology 07/2012; 73(10):1017-22. DOI:10.1016/j.humimm.2012.07.325 · 2.14 Impact Factor
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