Differential effects of myeloid dendritic cells retrovirally transduced to express mammalian or viral interleukin-10 on cytotoxic T lymphocyte and natural killer cell functions and resistance to tumor growth.
BACKGROUND
Genetic engineering of dendritic cells (DC) to express immunosuppressive molecule(s) offers potential for therapy of allograft rejection and autoimmune disease. Viral (v) interleukin (IL)-10, encoded by the Epstein-Barr virus, is highly homologous to mammalian (m) IL-10, but lacks certain of its T-cell stimulatory activities. Our aim was to evaluate and compare the influence of vIL-10 and mIL-10 gene transfer on the T-cell and natural killer (NK) cell stimulatory activity of DC, and their impact on the growth of transplantable tumors.


METHODS
Myeloid DC progenitors, propagated from the bone marrow of C57BL/6J (H2b) mice in granulocyte-macrophage colony-stimulating factor + IL-4, were transduced using retroviral supematant from the BOSC ecotropic packaging cell line. The function of the IL-b gene-modified DC was assessed by examining their ability to induce naive allogeneic T-cell proliferation and cytotoxic T lymphocyte (CTL) generation. MCA205 (H2b) sarcoma cells mixed with either vIL-10-, mIL-10-, or Zeo (control gene)-transduced DC were inoculated intradermally into C57BL/6J (syngeneic) or BALB/cJ (H2d) (allogeneic) recipients, which were monitored for tumor growth. The role of specific host effector cell populations in tumor resistance was determined by antibody depletion.


RESULTS
Compared with control gene-modified DC, both vIL-10- and mIL-10-transduced DC, which secreted the transgene product, showed reduced surface expression of MHC class II and costimulatory molecules, and impaired ability to induce T-cell proliferation. vIL-10-transduced DC were also inhibited with respect to CTL induction but did not affect the generation of NK cells. By contrast, mIL-10-transduced DC augmented CTL generation and NK cell activity. In the tumor transplant model, vIL-10-transduced DC enhanced tumor growth both in syngeneic and allogeneic hosts, whereas mIL-10-transduced cells inhibited tumor development. Depletion of CD4+ or CD8+ T cells or NK cells in mice given mIL-10-transduced DC reversed this therapeutic effect.


CONCLUSIONS
mIL-10 gene-modified myeloid DC promote CTL and NK cell-mediated responses and inhibit tumor growth. By contrast, vIL-10-engineered DC, which elicit diminished CTL responses and do not promote NK cell activity, seem to have therapeutic potential for inhibition of T cell-mediated immunity.
Takayama
T
T
Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
Tahara
H
H
Thomson
A W
AW
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology* / Q000821:virology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology*; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000166:cytology; D019139:Tumor Escape / Q000187:drug effects / Q000502:physiology
D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10