International Immunology Advance Access originally published online on August 4, 2009
International Immunology 2009 21(9):1089-1100; doi:10.1093/intimm/dxp074
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Induction of IL-10- and IFN-
-producing T-cell responses by autoreactive T-cells expressing human T-cell leukemia virus type I Tax
1 Department of Immunotherapeutics
2 Department of Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
3 Department of Veterinary Hygiene, Faculty of Agriculture, Yamaguchi University, Yamaguchi 753-8515, Japan
4 Division of Molecular Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
Correspondence to: M. Kannagi; E-mail: kann.impt{at}tmd.ac.jp
Human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell leukemia, HTLV-I-associated myelopathy/tropical spastic paraparesis and various autoimmune-like disorders. T-cell immune suppression is also associated with HTLV-I infection. Mechanisms of diverse immune dysregulation in HTLV-I infection are obscure. Here, we investigated a potential link between autoimmunity and immune suppression in HTLV-I infection. G14, an IL-2-dependent HTLV-I-negative CD4+CD8+ T-cell line previously established from an HTLV-I-infected rat, constantly proliferated and produced IFN-
. IFN- production by G14 cells was dependent on interactions between CD4 and MHC-II, suggesting that G14 cells recognized self-antigens presented by MHC-II on themselves. To examine immune response to G14 cells, we inoculated G14 cells into syngeneic naive rats. Interestingly, T-cells isolated from these rats vigorously proliferated when stimulated with G14-Tax cells that stably expressed HTLV-I Tax, but not with G14 cells. G14-Tax-mediated T-cell proliferation was abrogated by antibodies to CD80 and CD86 that were up-regulated in G14-Tax cells. T-cells propagated by repetitive G14-Tax cell stimulations in culture with IL-2 expressed CD4, CD25 and cytolytic T lymphocyte-associated antigen 4 (CTLA-4), produced abundant amounts of IL-10 and IFN- in response to G14 cells and suppressed growth of G14 cells mainly through supernatant-mediated mechanisms. Similar IL-10- and IFN--producing CD4+CD25+CTLA-4+ T-cells were predominantly induced in culture of splenocytes from HTLV-I-infected rats following stimulation with G14-Tax cells. These results implied that expression of Tax in the otherwise low immunogenic autoreactive T-cells induced IL-10- and IFN--producing T-cell responses with regulatory effects against the autoreactive cells. Our findings provide new insights into the complex immune conditions underlying HTLV-I-associated diseases.
Keywords: ATL, autoimmunity, immune suppression, inducible Treg, viral infection
Transmitting editor: S. Koyasu
Received 15 January 2009, accepted 10 July 2009.