IL-15, in synergy with RAE-1ε, stimulates TCR‑independent proliferation and activation of CD8+ T cells

Qian,Li; Zhang,Yue; Pan,Xin-Yuan; Ji,Ming-Chun; Gong,Wei-Juan; Tian,Fang

doi:10.3892/ol.2011.495

IL-15, in synergy with RAE-1ε, stimulates TCR‑independent proliferation and activation of CD8+ T cells

Authors:
- Li Qian
- Yue Zhang
- Xin-Yuan Pan
- Ming-Chun Ji
- Wei-Juan Gong
- Fang Tian
View Affiliations

Affiliations: Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225001, P.R. China, Department of General Surgery, Shanghai East Hospital, Tongji University, Shanghai 200120, P.R. China
Published online on: November 25, 2011 https://doi.org/10.3892/ol.2011.495
Pages: 472-476

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

CD8+ T cells play critical roles in immunosurveillance by killing malignant or virally infected cells. Interleukin 15 (IL-15) is a critical cytokine for promoting proliferation and the effector capacity of CD8+ T cells, and has been used to support the growth of CD8+ T cells in cellular therapies of neoplastic diseases. Recent studies have shown that IL-15, in synergy with other cytokines, such as IL-6, enhances the T-cell receptor (TCR)-independent proliferation and function of CD8+ T cells. The aim of the present study was to investigate the role of BaF3-mb15-RAE cells in stimulating mouse CD8+ T cells. BaF3 cells were cultured and B16F10 cells were grown in DMEM. MTT assay was used to detect the proliferation of CD8+ T cells. Cells were analyzed using flow cytometry. The results showed that IL-15 synergistically acts with another T-cell stimulatory molecule, RAE1ε, to potently promote the proliferation of CD8+ T cells, induce CD8+ T-cell activation and enhance granzyme B and interferon-γ (IFN-γ) production in the absence of signaling via the TCR. Moreover, IL-15 in combination with RAE1ε resulted in a cooperative effect on CD8+ T-cell-mediated cytotoxicity against B16F10 tumor cells. Thus, results of the present study showed that IL-15, in synergy with RAE1ε, enhances the TCR-independent effector function of CD8+ T cells in vitro, which may be useful in the cellular immunotherapy of cancer.

View Figures

View References

1	Elpek KG, Rubinstein MP, Bellemare-Pelletier A, Goldrath AW and Turley SJ: Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Ralpha complexes. Proc Natl Acad Sci USA. 107:21647–21652. 2010. View Article : Google Scholar
2	Stonier SW, Ma LJ, Castillo EF and Schluns KS: Dendritic cells drive memory CD8 T cell homeostasis via IL-15 transpresentation. Blood. 112:4546–4554. 2008. View Article : Google Scholar : PubMed/NCBI
3	Kokaji AI, Hockley DL and Kane KP: IL-15 transpresentation augments CD8⁺ T cell activation and is required for optimal recall responses by central memory CD8⁺ T cells. J Immunol. 180:4391–401. 2008.PubMed/NCBI
4	Stonier SW and Schluns KS: Trans-presentation: a novel mechanism regulating IL-15 delivery and responses. Immunol Lett. 127:85–92. 2010. View Article : Google Scholar : PubMed/NCBI
5	Dubois S, Mariner J, Waldmann TA and Tagaya Y: IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity. 17:537–547. 2002.
6	Mortier E, Quéméner A, Vusio P, Lorenzen I, Boublik Y, Grötzinger J, Plet A and Jacques Y: Soluble interleukin-15 receptor α (IL-15Rα)-sushi as a selective and potent agonist of IL-15 action through IL-15Rβ/γ: hyperagonist IL-15xIL-15Rα fusion proteins. J Biol Chem. 281:1612–1619. 2006.
7	Dubois S, Patel HJ, Zhang M, Waldmann TA and Müller JR: Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8⁺/CD44^high T cells and its antitumor action. J Immunol. 180:2099–2106. 2008. View Article : Google Scholar : PubMed/NCBI
8	Epardaud M, Elpek KG, Rubinstein MP, Yonekura AR, Bellemare-Pelletier A, Bronson R, Hamerman JA, Goldrath AW and Turley SJ: Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8⁺ T cells. Cancer Res. 68:2972–2983. 2008. View Article : Google Scholar : PubMed/NCBI
9	Stoklasek TA, Schluns KS and Lefrançois L: Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol. 177:6072–6080. 2006. View Article : Google Scholar : PubMed/NCBI
10	Verdeil G, Marquardt K, Surh CD and Sherman LA: Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy. Proc Natl Acad Sci USA. 105:16683–16688. 2008. View Article : Google Scholar : PubMed/NCBI
11	Rowley J, Monie A, Hung CF and Wu TC: Inhibition of tumor growth by NK1.1⁺ cells and CD8⁺ T cells activated by IL-15 through receptor beta/common gamma signaling in trans. J Immunol. 181:8237–8247. 2008.PubMed/NCBI
12	Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR and Raulet DH: The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity. 17:19–29. 2002. View Article : Google Scholar : PubMed/NCBI
13	Diefenbach A, Jamieson AM, Liu SD, Shastri N and Raulet DH: Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 1:119–126. 2000. View Article : Google Scholar : PubMed/NCBI
14	Raulet DH: Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 3:781–790. 2003. View Article : Google Scholar : PubMed/NCBI
15	González S, López-Soto A, Suarez-Alvarez B, López-Vázquez A and López-Larrea C: NKG2D ligands: key targets of the immune response. Trends Immunol. 29:397–403. 2008.PubMed/NCBI
16	Markiewicz MA, Carayannopoulos LN, Naidenko OV, Matsui K, Burack WR, Wise EL, Fremont DH, Allen PM, Yokoyama WM, Colonna M and Shaw AS: Costimulation through NKG2D enhances murine CD8⁺ CTL function: similarities and differences between NKG2D and CD28 costimulation. J Immunol. 175:2825–2833. 2005. View Article : Google Scholar : PubMed/NCBI
17	Maasho K, Opoku-Anane J, Marusina AI, Coligan JE and Borrego F: NKG2D is a costimulatory receptor for human naive CD8⁺ T cells. J Immunol. 174:4480–4484. 2005. View Article : Google Scholar : PubMed/NCBI
18	Roberts AI, Lee L, Schwarz E, Groh V, Spies T, Ebert EC and Jabri B: NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol. 167:5527–5530. 2001. View Article : Google Scholar : PubMed/NCBI
19	Qian L, Ji MC, Pan XY, Gong WJ, Tian F and Duan QF: Construction of a plasmid for co-expression of mouse membrane-bound form of IL-15 and RAE-1ɛ and its biological activity. Plasmid. 65:239–245. 2011.PubMed/NCBI
20	Kim GG, Donnenberg VS, Donnenberg AD, Gooding W and Whiteside TL: A novel multiparametric flow cytometry-based cytotoxicity assay simultaneously immunophenotypes effector cells: comparisons to a 4 h 51Cr-release assay. J Immunol Methods. 325:51–66. 2007. View Article : Google Scholar
21	Cho BK, Rao VP, Ge Q, Eisen HN and Chen J: Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med. 192:549–556. 2000. View Article : Google Scholar : PubMed/NCBI
22	Ramanathan S, Gagnon J, Dubois S, Forand-Boulerice M, Richter MV and Ilangumaran S: Cytokine synergy in antigen-independent activation and priming of naive CD8⁺ T lymphocytes. Crit Rev Immunol. 29:219–239. 2009. View Article : Google Scholar : PubMed/NCBI
23	Ramanathan S, Gagnon J and Ilangumaran S: Antigen-nonspecific activation of CD8⁺ T lymphocytes by cytokines: relevance to immunity, autoimmunity, and cancer. Arch Immunol Ther Exp (Warsz). 56:311–323. 2008.PubMed/NCBI
24	Gagnon J, Ramanathan S, Leblanc C, Cloutier A, McDonald PP and Ilangumaran S: IL-6, in synergy with IL-7 or IL-15, stimulates TCR-independent proliferation and functional differentiation of CD8⁺ T lymphocytes. J Immunol. 180:7958–7968. 2008. View Article : Google Scholar : PubMed/NCBI
25	Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, Berzofsky JA and Leonard WJ: Synergy of IL-21 and IL-15 in regulating CD8⁺ T cell expansion and function. J Exp Med. 201:139–148. 2005. View Article : Google Scholar : PubMed/NCBI
26	Kovanen PE and Leonard WJ: Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev. 202:67–83. 2004. View Article : Google Scholar
27	Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD and Sprent J: Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci USA. 103:9166–9171. 2006.PubMed/NCBI
28	Burkett PR, Koka R, Chien M, Chai S, Boone DL and Ma A: Coordinate expression and trans presentation of interleukin (IL)-15Rα and IL-15 supports natural killer cell and memory CD8⁺ T cell homeostasis. J Exp Med. 200:825–834. 2004.PubMed/NCBI
29	Schluns KS, Klonowski KD and Lefrançois L: Transregulation of memory CD8 T-cell proliferation by IL-15Rα⁺ bone marrow-derived cells. Blood. 103:988–994. 2004.PubMed/NCBI
30	Zaft T, Sapoznikov A, Krauthgamer R, Littman DR and Jung S: CD11c^high dendritic cell ablation impairs lymphopenia-driven proliferation of naive and memory CD8⁺ T Cells. J Immunol. 175:6428–6435. 2005.
31	Alves NL, Hooibrink B, Arosa FA and van Lier RA: IL-15 induces antigen-independent expansion and differentiation of human naive CD8⁺ T cells in vitro. Blood. 102:2541–2546. 2003. View Article : Google Scholar : PubMed/NCBI
32	Chang DZ, Wu Z and Ciardelli TL: A point mutation in interleukin-2 that alters ligand internalization. J Biol Chem. 271:13349–13355. 1996. View Article : Google Scholar : PubMed/NCBI
33	Kobayashi H, Dubois S, Sato N, Sabzevari H, Sakai Y, Waldmann TA and Tagaya Y: The role of trans-cellular IL-15-presentation in the activation of NK-mediated killing, which leads to enhanced tumor immune surveillance. Blood. 105:721–727. 2005. View Article : Google Scholar : PubMed/NCBI
34	Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR and Spies T: Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol. 2:255–260. 2001.
35	Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH and Jabri B: Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 21:357–366. 2004. View Article : Google Scholar : PubMed/NCBI
36	Budagian V, Bulanova E, Paus R and Bulfone-Paus S: IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev. 17:259–280. 2006. View Article : Google Scholar : PubMed/NCBI