IL-15 serves as a costimulator in determining the activity of autoreactive CD8 T cells in an experimental mouse model of graft-versus-host-like disease.
To elucidate the mechanisms controlling peripheral tolerance, we established two transgenic (Tg) mouse strains expressing different levels of membrane-bound OVA (mOVA) as a skin-associated self-Ag. When we transferred autoreactive TCR-Tg CD8 T cells (OT-I cells), keratin 14 (K14)-mOVA(high) Tg mice developed autoreactive skin disease (graft-vs-host disease (GVHD)-like skin lesions) while K14-mOVA(low) Tg mice did not. OT-I cells in K14-mOVA(high) Tg mice were fully activated with full development of effector function. In contrast, OT-I cells in K14-mOVA(low) Tg mice proliferated but did not gain effector function. Exogenous IL-15 altered the functional status of OT-I cells and concomitantly induced disease in K14-mOVA(low) Tg mice. Conversely, neutralization of endogenous IL-15 activity in K14-mOVA(high) Tg mice attenuated GVHD-like skin lesions induced by OT-I cell transfer. Futhermore, K14-mOVA(high) Tg mice on IL-15 knockout or IL-15Ralpha knockout backgrounds did not develop skin lesions after adoptive transfer of OT-I cells. These results identify IL-15 as an indispensable costimulator that can determine the functional fate of autoreactive CD8 T cells and whether immunity or tolerance ensues, and they suggest that inhibition of IL-15 function may be efficacious in blocking expression of autoimmunity where a breach in peripheral tolerance is suspected.
Miyagawa
Fumi
F
Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Tagaya
Yutaka
Y
Kim
Brian S
BS
Patel
Hiral J
HJ
Ishida
Kazuto
K
Ohteki
Toshiaki
T
Waldmann
Thomas A
TA
Katz
Stephen I
SI
D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology
D019409:Interleukin-15; D010047:Ovalbumin