Interleukin-2 activated microglia engulf tumor infiltrating T cells in the central nervous system.
Interleukin-2 (IL-2) has been utilized to treat cancer patient. However, recent studies disclosed that IL-2 induces T cell death. To clarify IL-2 induced T cell apoptosis at tumor sites in the central nervous system (CNS), we utilized an intracranial implantation of IL-2 cDNA transduced murine tumor cells and examined freshly recovered tumor infiltrating T lymphocytes (TIL) with a magnetic beads separation method. CD8(+) TIL recovered from the IL-2 therapy model had three times more apoptosis than a control group, tumor weights at day 12 decreased (0.016 versus 0.041 g/mouse) and the number of TIL per gram of tumor tissue increase more than six times by IL-2 therapy (5.69x10(6) versus 33.7x10(7) cells per mouse). In addition, both activation marker expressions (CD25 and CD69) and cytokine message levels (interferon gamma, and tumor necrosis factor alpha) on CD8(+) TIL decrease in the IL-2 therapy model. Moreover, we detected higher CD8beta message levels in purified tumors associated with F4/80(+) cells from the IL-2 model than the control by a one-step RT-PCR method. Finally, we observed many CD8beta(+) TIL surrounded by numerous infiltrating F4/80(+) cells in the tumor tissues of the IL-2 therapy model by immuno-fluorescence microscopic analysis. Our data show that IL-2 sensitization of apoptosis induction for CD8(+) TIL occurred and the apoptotic T cells were eliminated by F4/80(+) microglia in the CNS. Moreover, this is the first report describing in situ elimination of TIL by F4/80(+) phagocytic cells in the CNS.
Tamakawa
Noriyuki
N
Department of Neurosurgery, Gifu University School of Medicine, Gifu, Japan.
Saio
Masanao
M
Suwa
Tatsuhiko
T
Ohe
Naoyuki
N
Yoshimura
Shin-Ichi
S
Iwama
Toru
T
Shinoda
Jun
J
Sakai
Noboru
N
Takami
Tsuyoshi
T
D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism* / Q000627:therapeutic use; D037181:Lectins, C-Type; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099192:CD69 Antigens
D017304:Annexin A5; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018076:DNA, Complementary; D007371:Interferon-gamma; D007376:Interleukin-2; D037181:Lectins, C-Type; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens