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Prot Cell    2011, Vol. 2 Issue (7) : 585-599    https://doi.org/10.1007/s13238-011-1080-8      PMID: 21822803
RESEARCH ARTICLE
Selective expansion and enhanced anti-tumor effect of antigen-specific CD4+ T cells by retrovirus-mediated IL-15 expression
Jizhou Lv1,2, Ning Tao1, Hao Wu1, Xiaoman Liu1, Xia Xu1, Yingxin Xu3, Zhihai Qin1()
1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China; 2. Graduate School of Chinese Academy of Sciences, Beijing 100080, China; 3. Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing 100853, China
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Abstract

Mounting evidence has demonstrated that CD4+ T cells play an important role in anti-tumor immune responses. Thus, adoptive transfer of these cells may have great potential for anti-cancer therapy. However, due to the difficulty to generate sufficient tumor-specific CD4+ T cells, the use of CD4+ T cells in tumor therapy is limited. It has been found that IL-15 transfection enhances the proliferation and anti-tumor activity of tumor-specific CD8+ T cells, but the effect of IL-15 transfection on CD4+ T cells remains unknown. Here, the effects of retrovirus-mediated IL-15 expression in Ova-specific CD4+ T cells from Do11.10 mice were evaluated and it was discovered that IL-15 transfected CD4+ T cells expressed both soluble and membrane-bound IL-15. Retrovirus-mediated IL-15 expression led to a selective expansion of antigen-specific CD4+ T cells by inhibiting their apoptosis. Invivo IL-15 transfected CD4+ T cells were more effective in suppressing tumor growth than control retroviral vector transfected ones. To ensure the safety of the method, the employment of thymidine kinase gene made it possible to eliminate these transgenic CD4+ T cells following ganciclovir treatment. Together, we show that IL-15 transfection induced a selective expansion of antigen-specific CD4+ T cells ex vivo and enhanced their tumor-suppression effects in vivo. This has an important significance for improving the efficacy of adoptive T cell therapy.
Keywords CD4+ T cells      retrovirus vector      IL-15      tumor therapy     
Corresponding Author(s): Qin Zhihai,Email:zhihai@ibp.ac.cn   
Issue Date: 01 July 2011
 Cite this article:   
Jizhou Lv,Ning Tao,Hao Wu, et al. Selective expansion and enhanced anti-tumor effect of antigen-specific CD4+ T cells by retrovirus-mediated IL-15 expression[J]. Prot Cell, 2011, 2(7): 585-599.
 URL:  
https://academic.hep.com.cn/pac/EN/10.1007/s13238-011-1080-8
https://academic.hep.com.cn/pac/EN/Y2011/V2/I7/585
Fig.1  Construction of IL-15 expression retroviral vector.
(A) Schema of the retroviral vectors pTK-IL15, pTK-GFP and pTK-Con. LTR, long terminal repeat; HYTK, a fusion gene confers hygromycin B resistance and thymidine kinase activity; P, the elongation factor 1 promoter; ψ, retroviral packaging signal. (B) RT-PCR to assess mRNA levels of hIL-15 and thymidine kinase. The β-actin gene was used to demonstrate the quality of RNA. Total RNA was isolated from CD4 T cells transfected with pTK-Con, pTK-IL15 vectors or untreated CD4 T cells (control). (C) ELISA assay to assess hIL-15 protein level. The culture supernatant of pTK-con Con, pTK-IL15 transfected CD4 T cells or untreated CD4T cells was collected. The quantity of hIL-15 was determined in the culture supernatant at the indicated time and measured by specific ELISA. Data are representative of three experiments. ** <0.01.
Fig.1  Construction of IL-15 expression retroviral vector.
(A) Schema of the retroviral vectors pTK-IL15, pTK-GFP and pTK-Con. LTR, long terminal repeat; HYTK, a fusion gene confers hygromycin B resistance and thymidine kinase activity; P, the elongation factor 1 promoter; ψ, retroviral packaging signal. (B) RT-PCR to assess mRNA levels of hIL-15 and thymidine kinase. The β-actin gene was used to demonstrate the quality of RNA. Total RNA was isolated from CD4 T cells transfected with pTK-Con, pTK-IL15 vectors or untreated CD4 T cells (control). (C) ELISA assay to assess hIL-15 protein level. The culture supernatant of pTK-con Con, pTK-IL15 transfected CD4 T cells or untreated CD4T cells was collected. The quantity of hIL-15 was determined in the culture supernatant at the indicated time and measured by specific ELISA. Data are representative of three experiments. ** <0.01.
Fig.2  CD4 T cells transfected with IL-15 retroviral vector express intracellular and membrane-bound IL-15.
(A) Expression of intracellular IL-15 by retrovirus transfected CD4 T cells. Intracellular IL-15 was detected in permeabilized pTK-IL15 transfected CD4 T cells (solid black line) and pTK-Con transfected CD4 T cells (solid gray line) by anti-IL15 mAb. The pTK-IL15 transfected CD4 T cells stained with isotype control mAb were taken as negative control (dotted line). (B) Expression of membrane-bound IL-15 by retrovirus transfected CD4 T cells. Membrane-bound IL-15 was detected on pTK-IL15 transfected CD4 T cells (solid black line), pTK-Con transfected CD4 T cells (solid gray line) by anti-IL15 mAb. The pTK-IL15 transfected CD4 T cells stained with isotype mAb were taken as negative control (dotted line). The number above bracketed lines indicates the percentage for cells positive for PE-labeled IL-15. (C) Transfection efficiency determination of pTK-GFP retroviral vector. Flow-cytometry analysis (dots) of GFP production in pTK-GFP transfected Do11.10 CD4 T cells and pTK-Con transfected Do11.10 CD4 T cells (as control). The number above outlined areas indicates the percentage of GFP CD4 T cells. Data are representative of three experiments.
Fig.2  CD4 T cells transfected with IL-15 retroviral vector express intracellular and membrane-bound IL-15.
(A) Expression of intracellular IL-15 by retrovirus transfected CD4 T cells. Intracellular IL-15 was detected in permeabilized pTK-IL15 transfected CD4 T cells (solid black line) and pTK-Con transfected CD4 T cells (solid gray line) by anti-IL15 mAb. The pTK-IL15 transfected CD4 T cells stained with isotype control mAb were taken as negative control (dotted line). (B) Expression of membrane-bound IL-15 by retrovirus transfected CD4 T cells. Membrane-bound IL-15 was detected on pTK-IL15 transfected CD4 T cells (solid black line), pTK-Con transfected CD4 T cells (solid gray line) by anti-IL15 mAb. The pTK-IL15 transfected CD4 T cells stained with isotype mAb were taken as negative control (dotted line). The number above bracketed lines indicates the percentage for cells positive for PE-labeled IL-15. (C) Transfection efficiency determination of pTK-GFP retroviral vector. Flow-cytometry analysis (dots) of GFP production in pTK-GFP transfected Do11.10 CD4 T cells and pTK-Con transfected Do11.10 CD4 T cells (as control). The number above outlined areas indicates the percentage of GFP CD4 T cells. Data are representative of three experiments.
Fig.3  IL-15 modification leads to enhanced CD4 T cells recovery in the presence of IL-2.
(A) Cell counting assay to determine the recovery of CD4 T cells. Two days after retroviral vector transfection, CD4 T cells transfected with IL-15 retroviral vector were cultured with recombinant hIL-2 (10 ng/mL) (?) or without hIL-2 (○). And the CD4 T cells transfected with pTK-Con retroviral vector were cultured with hIL-2 (10 ng/mL) (?) or without hIL-2 (□). The number of CD4 T cells was counted every day. (B) MTT assay to determine the recovery of CD4 T cells. The CD4 T cells transfected with pTK-IL15 retroviral vector (□) or pTK-Con retroviral vector (?) were cultured in 24-well plate at a density of 2 × 10/well in the presence of hIL-2. The quantity of CD4 T cells was determined by MTT assay. Data are representative of three experiments.
Fig.3  IL-15 modification leads to enhanced CD4 T cells recovery in the presence of IL-2.
(A) Cell counting assay to determine the recovery of CD4 T cells. Two days after retroviral vector transfection, CD4 T cells transfected with IL-15 retroviral vector were cultured with recombinant hIL-2 (10 ng/mL) (?) or without hIL-2 (○). And the CD4 T cells transfected with pTK-Con retroviral vector were cultured with hIL-2 (10 ng/mL) (?) or without hIL-2 (□). The number of CD4 T cells was counted every day. (B) MTT assay to determine the recovery of CD4 T cells. The CD4 T cells transfected with pTK-IL15 retroviral vector (□) or pTK-Con retroviral vector (?) were cultured in 24-well plate at a density of 2 × 10/well in the presence of hIL-2. The quantity of CD4 T cells was determined by MTT assay. Data are representative of three experiments.
Fig.4  IL-15 selectively expands antigen-specific CD4 T cells.
Do11.10 CD4 T cells were co-cultured at different ratios (from 1∶10 to 1∶10) thawed non-specific CD4 T cells. The initial number of non-specific CD4 T cells was 5 × 10 and the number of specific CD4 T cells was adjusted from 5 × 10 to 5 following the different ratios. The numbers of living CD4 KJ26 T cells (specific CD4 T cells) and CD4 KJ26 (non-specific CD4 T cells) were confirmed by guava staining assay on 7 day of culture. (A) The numbers of antigen-specific CD4 T cells. (B) The numbers of non-specific CD4 T cells. (C) Flow cytometry analysis to determine the percentages of antigen-specific CD4 T cells (dots). Numbers above bracketed lines indicate the percentages of specific CD4 cells. (D) The percentages of specific CD4 T cells. Data are representative of four experiments.
Fig.4  IL-15 selectively expands antigen-specific CD4 T cells.
Do11.10 CD4 T cells were co-cultured at different ratios (from 1∶10 to 1∶10) thawed non-specific CD4 T cells. The initial number of non-specific CD4 T cells was 5 × 10 and the number of specific CD4 T cells was adjusted from 5 × 10 to 5 following the different ratios. The numbers of living CD4 KJ26 T cells (specific CD4 T cells) and CD4 KJ26 (non-specific CD4 T cells) were confirmed by guava staining assay on 7 day of culture. (A) The numbers of antigen-specific CD4 T cells. (B) The numbers of non-specific CD4 T cells. (C) Flow cytometry analysis to determine the percentages of antigen-specific CD4 T cells (dots). Numbers above bracketed lines indicate the percentages of specific CD4 cells. (D) The percentages of specific CD4 T cells. Data are representative of four experiments.
Days of cultureTransfected T cellsRatios of antigen-specific CD4+ T cells to non-specific CD4+ T cells
1∶1021∶1031∶1041∶1051∶106
1st dayNo transfection1%0.1%0.01%0.001%0.0001%
3rd dayNo transfection2.81%±0.65%0.53%±0.19%No dataNo dataNo data
5th daypTK-Con4.32%±0.92%1.16%±0.32%0.17%±0.09%No dataNo data
pTK-IL153.85%±0.43%1.13%±0.26%0.24%±0.06%No dataNo data
7th daypTK-Con9.39%±0.96%2.25%±0.35%0.31%±0.09%0.19%±0.07%0.10%±0.08%
pTK-IL158.53%±1.35%2.05%±0.31%0.94%±0.14%0.72%±0.08%0.48%±0.11%
9th daypTK-Con21.71%±4.38%5.36%±1.02%0.62%±0.23%0.45%±0.17%0.43%±0.16%
pTK-IL1519.22%±3.21%5.05%±0.94%2.15%±0.41%1.58%±0.22%1.14%±0.24%
11th daypTK-Con57.51%±7.52%13.07%±2.21%1.18%±0.41%0.75%±0.21%1.06%±0.18%
pTK-IL1554.08%±8.21%12.68%±3.21%3.94%±0.81%2.95%±0.21%2.54%±0.61%
Tab.1  The percentages of antigen-specific CD4 T cells in T cell culture after retroviral transfection
Fig.5  Retrovirus-mediated IL-15 expression protects CD4 T cells from apoptosis .
(A) IL-15 transfection could not accelerate the proliferation rate of CD4 T cells while recombinant hIL-15 could. CD4 T cells transfected with pTK-IL15 were inoculated without hIL-15 while pTK-Con transfected CD4 T cells were inoculated with different doses of recombinant hIL-15 (from 50 pg/mL to 200 ng/mL) as control. [H] thymidine incorporation was determined three days later. (B) IL-15 transfection did not accelerate the proliferation rate of CD4 T cells in the presence of hIL-2. CD4 T cells transfected with pTK-IL15 and CD4 T cells transfected with pTK-Con were cultured with hIL-2 (10 ng/mL), while CD4 T cells cultured without additional cytokine were taken as control. [H] thymidine incorporation was determined three days later. (C) CD4 T cells transfected with pTK-IL15 resisted activation-induced cell death (AICD). CD4 T cells transfected with pTK-IL15 and CD4 T cells transfected with pTK-Con were cultured for 16 h in the presence of plate-bound anti-CD3 and soluble anti-CD28 without exogenous cytokine. Evaluation of apoptosis through flow cytometry of isolated CD4 KJ26 T cells with an anti-Annexin-V mAb. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. (D) CD4 T cells transfected with pTK-IL15 resisted AICD in the presence of recombinant hIL-2. CD4 T cells transfected with pTK-IL15 and CD4 T cells transfected with pTK-Con were cultured in the presence of anti-CD3 and anti-CD28 with 10 ng/mL recombinant hIL-2 for 16 h. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. Results are from three representative experiments. ** <0.01, * <0.05 and N.S. (>0.05)
Fig.5  Retrovirus-mediated IL-15 expression protects CD4 T cells from apoptosis .
(A) IL-15 transfection could not accelerate the proliferation rate of CD4 T cells while recombinant hIL-15 could. CD4 T cells transfected with pTK-IL15 were inoculated without hIL-15 while pTK-Con transfected CD4 T cells were inoculated with different doses of recombinant hIL-15 (from 50 pg/mL to 200 ng/mL) as control. [H] thymidine incorporation was determined three days later. (B) IL-15 transfection did not accelerate the proliferation rate of CD4 T cells in the presence of hIL-2. CD4 T cells transfected with pTK-IL15 and CD4 T cells transfected with pTK-Con were cultured with hIL-2 (10 ng/mL), while CD4 T cells cultured without additional cytokine were taken as control. [H] thymidine incorporation was determined three days later. (C) CD4 T cells transfected with pTK-IL15 resisted activation-induced cell death (AICD). CD4 T cells transfected with pTK-IL15 and CD4 T cells transfected with pTK-Con were cultured for 16 h in the presence of plate-bound anti-CD3 and soluble anti-CD28 without exogenous cytokine. Evaluation of apoptosis through flow cytometry of isolated CD4 KJ26 T cells with an anti-Annexin-V mAb. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. (D) CD4 T cells transfected with pTK-IL15 resisted AICD in the presence of recombinant hIL-2. CD4 T cells transfected with pTK-IL15 and CD4 T cells transfected with pTK-Con were cultured in the presence of anti-CD3 and anti-CD28 with 10 ng/mL recombinant hIL-2 for 16 h. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. Results are from three representative experiments. ** <0.01, * <0.05 and N.S. (>0.05)
Fig.6  Prolonged survival of pTK-IL15 transfected CD4 T cells in spleen.
(A) Detecting the transferred CD4 T cells in spleen. Retroviral vector transfected CD4 T cells were injected i.v. into TS/A-mOva bearing BALB/c mice and lymphocytes from spleen of the recipient mice were analyzed three days, 45 days and 60 days after T cell transfer. Transferred CD4 T cells were traced by KJ26 mAb. The dot plots were gated on total CD4 T lymphocytes and the numbers represented the percentages of the CD4 KJ26 population. (B) Proliferation of transferred CD4 T cells in spleen. Continuous treatment with BrdU was initiated after T cells infusion and lasted for three days before the harvesting of spleens. CD4 KJ26 T cells were gated and the numbers represented the percentages of the BrdU population. (C) Apoptosis of transferred CD4 T cells in spleen. Evaluation of apoptosis through flow cytometry of isolated CD4 KJ26 T cells in spleen with an anti-Annexin-V mAb three days after T cell infusion. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. Data from one representative experiment out of four are shown. N.S. >0.05, * <0.05.
Fig.6  Prolonged survival of pTK-IL15 transfected CD4 T cells in spleen.
(A) Detecting the transferred CD4 T cells in spleen. Retroviral vector transfected CD4 T cells were injected i.v. into TS/A-mOva bearing BALB/c mice and lymphocytes from spleen of the recipient mice were analyzed three days, 45 days and 60 days after T cell transfer. Transferred CD4 T cells were traced by KJ26 mAb. The dot plots were gated on total CD4 T lymphocytes and the numbers represented the percentages of the CD4 KJ26 population. (B) Proliferation of transferred CD4 T cells in spleen. Continuous treatment with BrdU was initiated after T cells infusion and lasted for three days before the harvesting of spleens. CD4 KJ26 T cells were gated and the numbers represented the percentages of the BrdU population. (C) Apoptosis of transferred CD4 T cells in spleen. Evaluation of apoptosis through flow cytometry of isolated CD4 KJ26 T cells in spleen with an anti-Annexin-V mAb three days after T cell infusion. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. Data from one representative experiment out of four are shown. N.S. >0.05, * <0.05.
Fig.7  Prolonged survival of pTK-IL15 transfected CD4 T cells in tumor.
(A) Detecting the transferred CD4 T cells in tumor. Retroviral vector transfected CD4 T cells were injected i.v. into TS/A-mOva bearing BALB/c mice and lymphocytes from tumor of the recipient mice were analyzed three days, 45 days and 60 days after transfer. Transferred CD4 T Cells were traced by KJ26 mAb. The dot plots were gated on total CD4 T lymphocytes and the numbers represented the percentages of the outlined CD4 KJ26 population. (B) Proliferation of transferred CD4 T cells in tumor. Continuous treatment with BrdU was initiated after adoptive CD4 T cells transfer and lasted for three days before the harvesting of tumors. CD4 KJ26 T cells were gated and the numbers represented the percentages of the outlined BrdU population. (C) Apoptosis of transferred CD4 T cells in spleen. Evaluation of apoptosis through flow cytometry of isolated CD4 KJ26 T cells in spleen with an anti-Annexin-V mAb three days after T cell infusion. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. Data from one representative experiment out of four are shown. N.S. >0.05, * <0.05.
Fig.7  Prolonged survival of pTK-IL15 transfected CD4 T cells in tumor.
(A) Detecting the transferred CD4 T cells in tumor. Retroviral vector transfected CD4 T cells were injected i.v. into TS/A-mOva bearing BALB/c mice and lymphocytes from tumor of the recipient mice were analyzed three days, 45 days and 60 days after transfer. Transferred CD4 T Cells were traced by KJ26 mAb. The dot plots were gated on total CD4 T lymphocytes and the numbers represented the percentages of the outlined CD4 KJ26 population. (B) Proliferation of transferred CD4 T cells in tumor. Continuous treatment with BrdU was initiated after adoptive CD4 T cells transfer and lasted for three days before the harvesting of tumors. CD4 KJ26 T cells were gated and the numbers represented the percentages of the outlined BrdU population. (C) Apoptosis of transferred CD4 T cells in spleen. Evaluation of apoptosis through flow cytometry of isolated CD4 KJ26 T cells in spleen with an anti-Annexin-V mAb three days after T cell infusion. Numbers above bracketed lines indicate the percentage of cells positive for Annexin-V. Data from one representative experiment out of four are shown. N.S. >0.05, * <0.05.
Fig.8  Efficient tumor suppression by pTK-IL15 transfected CD4 T cells.
(A) The growth of TS/A-mOva adenocarcinoma in mice infused with transfected CD4 T cells. Tumor-bearing mice were infused by an i.v. adoptive transfer of 5 × 10 pTK-IL15 transfected CD4 T cells (○, = 5) or pTK-Con transfected CD4 T cells (?, = 5) or just PBS (◆, = 5) as control. Shown here are mean tumor volumes with SDs. Tumor sizes of TS/A-mOva bearing mice were monitored for over 70 days after tumor incubation. (B) The survival of TS/A-mOva adenocarcinoma bearing mice. (C) The growth of J558L-mOva plasmacytoma in mice infused with transfected CD4 T cells. Tumor-bearing mice were infused by an i.v. adoptive transfer of pTK-IL15 transfected CD4 T cells (○, = 10) or pTK-Con transfected CD4 T cells (?, = 10) or just PBS (◆, = 6) as control. Tumor growth was followed. Shown here are mean tumor volumes plus SDs after tumor cell inoculation. (D) The survival of J558L-mOva plasmacytoma bearing mice. All data shown are representative of three independently performed experiments. ** <0.01 and * <0.05.
Fig.8  Efficient tumor suppression by pTK-IL15 transfected CD4 T cells.
(A) The growth of TS/A-mOva adenocarcinoma in mice infused with transfected CD4 T cells. Tumor-bearing mice were infused by an i.v. adoptive transfer of 5 × 10 pTK-IL15 transfected CD4 T cells (○, = 5) or pTK-Con transfected CD4 T cells (?, = 5) or just PBS (◆, = 5) as control. Shown here are mean tumor volumes with SDs. Tumor sizes of TS/A-mOva bearing mice were monitored for over 70 days after tumor incubation. (B) The survival of TS/A-mOva adenocarcinoma bearing mice. (C) The growth of J558L-mOva plasmacytoma in mice infused with transfected CD4 T cells. Tumor-bearing mice were infused by an i.v. adoptive transfer of pTK-IL15 transfected CD4 T cells (○, = 10) or pTK-Con transfected CD4 T cells (?, = 10) or just PBS (◆, = 6) as control. Tumor growth was followed. Shown here are mean tumor volumes plus SDs after tumor cell inoculation. (D) The survival of J558L-mOva plasmacytoma bearing mice. All data shown are representative of three independently performed experiments. ** <0.01 and * <0.05.
Fig.9  CD4 T cells transfected with pTK-IL15 could be eliminated by GCV treatment.
After infusion with pTK-IL15 transfected CD4 T cells or pTK-Con transfected CD4 T cells, mice were treated with GCV or PBS (as control) every day. Three days later, splenocytes were isolated and transferred CD4 T cells were detected by CD4 & KJ26 double staining. (A) Detecting the pTK-IL15 transfected CD4 T cells in GCV treated mice. CD4 T cells were gated and the numbers represented the percentages of the outlined CD4 KJ26 population. (B) Detecting the pTK-Con transfected CD4 T cells in GCV treated mice. CD4 T cells were gated and the numbers represented the percentages of the outlined CD4 KJ26 population. All data shown are representative of three independently performed experiments. ** <0.01.
Fig.9  CD4 T cells transfected with pTK-IL15 could be eliminated by GCV treatment.
After infusion with pTK-IL15 transfected CD4 T cells or pTK-Con transfected CD4 T cells, mice were treated with GCV or PBS (as control) every day. Three days later, splenocytes were isolated and transferred CD4 T cells were detected by CD4 & KJ26 double staining. (A) Detecting the pTK-IL15 transfected CD4 T cells in GCV treated mice. CD4 T cells were gated and the numbers represented the percentages of the outlined CD4 KJ26 population. (B) Detecting the pTK-Con transfected CD4 T cells in GCV treated mice. CD4 T cells were gated and the numbers represented the percentages of the outlined CD4 KJ26 population. All data shown are representative of three independently performed experiments. ** <0.01.
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