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CD8(+)NKT-like cells regulate the immune response by killing antigen-bearing DCs.

Wang C, Liu X, Li Z, Chai Y, Jiang Y, Wang Q, Ji Y, Zhu Z, Wan Y, Yuan Z, Chang Z, Zhang M - Sci Rep (2015)

Bottom Line: Further functional analyses show that CD8(+)NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner.Our study suggests that CD8(+)NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs.Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Tsinghua University School of Medicine, Beijing 100084, China.

ABSTRACT
CD1d-dependent NKT cells have been extensively studied; however, the function of CD8(+)NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8(+)NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8(+)NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8(+)NKT-like cell development is normal in CD1d(-/-) mice, which suggests that CD8(+)NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8(+)NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8(+)NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8(+)NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

No MeSH data available.


Related in: MedlinePlus

CD8+NKT-like cells involved in immune downregulation in vivo.(a) NKTGFP or NKTOVA cells were injected into naïve mice, which subsequently received immunization with GFP-DCs and OVA-DCs. Two weeks later, splenocytes from each group were co-cultured with GFP-DCs or OVA-DCs, and the TNF-alpha and IFN-gamma production levels were detected in the supernatant at 72 hours. These data are representative of three independent experiments (n = 8). (b,c) NKTGFP and NKTSV cells were pre-injected into RIP-OVA mice, which was subsequently injected peritoneally with OVA-specific CD8 T cells and GFP-DCs loaded with OT-I peptides. The blood glucose dynamics (b) and body weight (c) were measured in both conditions. These data are representative of two independent experiments (n = 8). ***P < 0.001.
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f6: CD8+NKT-like cells involved in immune downregulation in vivo.(a) NKTGFP or NKTOVA cells were injected into naïve mice, which subsequently received immunization with GFP-DCs and OVA-DCs. Two weeks later, splenocytes from each group were co-cultured with GFP-DCs or OVA-DCs, and the TNF-alpha and IFN-gamma production levels were detected in the supernatant at 72 hours. These data are representative of three independent experiments (n = 8). (b,c) NKTGFP and NKTSV cells were pre-injected into RIP-OVA mice, which was subsequently injected peritoneally with OVA-specific CD8 T cells and GFP-DCs loaded with OT-I peptides. The blood glucose dynamics (b) and body weight (c) were measured in both conditions. These data are representative of two independent experiments (n = 8). ***P < 0.001.

Mentions: Originally, we showed that GFP-DC immunization increased the number of CD8+ NKTGFP cells in mice. The in vitro data also suggested that CD8+ NKT-like cells might play a role in regulating DCs. Therefore, we further explored the regulatory function of CD8+ NKT-like cells in the immune response in vivo. The mice were first injected with NKTGFP or NKTOVA cells and subsequently received an immunization with both GFP-DCs and OVA-DCs. Two weeks later, splenocytes from each group were co-cultured with GFP-DCs or OVA-DCs for 72 h, and the level of cytokines secreted in the supernatant was determined. We found that, if the mice were pre-treated with NKTGFP, the splenocyte re-challenge by GFP-DCs yielded lower levels of TNF-α and IFN-γ compared with the cells re-challenged by OVA-DCs. Similar results were observed in mice immunized with NKTOVA cells (Fig. 6a). These data demonstrate that intervention with antigen-specific CD8+NKT-like cells kills specific antigen-bearing DCs and reduces their opportunity to stimulate immunocytes and down-regulate the immune response. RIP-OVA transgenic mice were also used to study the immunosuppressive effect of CD8+NKT-like cells. RIP-OVA transgenic mice, which express high levels of ovalbumin protein in their pancreas, were subjected to severe pancreatic islet damage when injected with CTLs activated by OVA257–264-loaded GFP-DCs and exhibited elevated blood glucose levels as well as lower body weight. However, pre-injection with NKTGFP, but not NKTSV, significantly inhibited the blood glucose increase (Fig. 6b) and body weight decrease (Fig. 6c).


CD8(+)NKT-like cells regulate the immune response by killing antigen-bearing DCs.

Wang C, Liu X, Li Z, Chai Y, Jiang Y, Wang Q, Ji Y, Zhu Z, Wan Y, Yuan Z, Chang Z, Zhang M - Sci Rep (2015)

CD8+NKT-like cells involved in immune downregulation in vivo.(a) NKTGFP or NKTOVA cells were injected into naïve mice, which subsequently received immunization with GFP-DCs and OVA-DCs. Two weeks later, splenocytes from each group were co-cultured with GFP-DCs or OVA-DCs, and the TNF-alpha and IFN-gamma production levels were detected in the supernatant at 72 hours. These data are representative of three independent experiments (n = 8). (b,c) NKTGFP and NKTSV cells were pre-injected into RIP-OVA mice, which was subsequently injected peritoneally with OVA-specific CD8 T cells and GFP-DCs loaded with OT-I peptides. The blood glucose dynamics (b) and body weight (c) were measured in both conditions. These data are representative of two independent experiments (n = 8). ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4569892&req=5

f6: CD8+NKT-like cells involved in immune downregulation in vivo.(a) NKTGFP or NKTOVA cells were injected into naïve mice, which subsequently received immunization with GFP-DCs and OVA-DCs. Two weeks later, splenocytes from each group were co-cultured with GFP-DCs or OVA-DCs, and the TNF-alpha and IFN-gamma production levels were detected in the supernatant at 72 hours. These data are representative of three independent experiments (n = 8). (b,c) NKTGFP and NKTSV cells were pre-injected into RIP-OVA mice, which was subsequently injected peritoneally with OVA-specific CD8 T cells and GFP-DCs loaded with OT-I peptides. The blood glucose dynamics (b) and body weight (c) were measured in both conditions. These data are representative of two independent experiments (n = 8). ***P < 0.001.
Mentions: Originally, we showed that GFP-DC immunization increased the number of CD8+ NKTGFP cells in mice. The in vitro data also suggested that CD8+ NKT-like cells might play a role in regulating DCs. Therefore, we further explored the regulatory function of CD8+ NKT-like cells in the immune response in vivo. The mice were first injected with NKTGFP or NKTOVA cells and subsequently received an immunization with both GFP-DCs and OVA-DCs. Two weeks later, splenocytes from each group were co-cultured with GFP-DCs or OVA-DCs for 72 h, and the level of cytokines secreted in the supernatant was determined. We found that, if the mice were pre-treated with NKTGFP, the splenocyte re-challenge by GFP-DCs yielded lower levels of TNF-α and IFN-γ compared with the cells re-challenged by OVA-DCs. Similar results were observed in mice immunized with NKTOVA cells (Fig. 6a). These data demonstrate that intervention with antigen-specific CD8+NKT-like cells kills specific antigen-bearing DCs and reduces their opportunity to stimulate immunocytes and down-regulate the immune response. RIP-OVA transgenic mice were also used to study the immunosuppressive effect of CD8+NKT-like cells. RIP-OVA transgenic mice, which express high levels of ovalbumin protein in their pancreas, were subjected to severe pancreatic islet damage when injected with CTLs activated by OVA257–264-loaded GFP-DCs and exhibited elevated blood glucose levels as well as lower body weight. However, pre-injection with NKTGFP, but not NKTSV, significantly inhibited the blood glucose increase (Fig. 6b) and body weight decrease (Fig. 6c).

Bottom Line: Further functional analyses show that CD8(+)NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner.Our study suggests that CD8(+)NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs.Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Tsinghua University School of Medicine, Beijing 100084, China.

ABSTRACT
CD1d-dependent NKT cells have been extensively studied; however, the function of CD8(+)NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8(+)NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8(+)NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8(+)NKT-like cell development is normal in CD1d(-/-) mice, which suggests that CD8(+)NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8(+)NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8(+)NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8(+)NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

No MeSH data available.


Related in: MedlinePlus