MHC class I and TCR avidity control the CD8 T cell response to IL-15/IL-15Rα complex.
IL-15 operates via a unique mechanism termed transpresentation. In this system, IL-15 produced by one cell type is bound to IL-15Rα expressed by the same cell and is presented to apposing cells expressing the IL-15Rβ/γC complex. We have shown that administering soluble IL-15Rα complexed with IL-15 can greatly enhance IL-15 activity. We now show that the naive CD8 T cell response to exogenous IL-15/IL-15Rα complex is MHC class I dependent. In the absence of β2 microglobulin, naive CD8 T cells scarcely proliferated in response to IL-15/IL-15Rα complex, whereas memory cells proliferated, although to a lesser extent, compared with levels in control mice. The loss of β2m or FcRn slightly reduced the extended half-life of IL-15/IL-15Rα complex, whereas FcRn deficiency only partially reduced the naive CD8 T cell proliferative response to IL-15/IL-15Rα complex. In addition, we demonstrated a link between TCR avidity and the ability of a T cell to respond to IL-15/IL-15Rα complex. Thus, T cells expressing low-avidity TCR responded poorly to IL-15/IL-15Rα complex, which correlated with a poor homeostatic proliferative response to lymphopenia. The inclusion of cognate peptide along with complex resulted in enhanced proliferation, even when TCR avidity was low. IL-15/IL-15Rα complex treatment, along with peptide immunization, also enhanced activation and the migratory ability of responding T cells. These data suggest that IL-15/IL-15Rα complex has selective effects on Ag-activated CD8 T cells. Our findings have important implications for directing IL-15/IL-15Rα complex-based therapy to specific Ag targets and illustrate the possible adjuvant uses of IL-15/IL-15Rα complex.
Department of Immunology, Center for Integrated Immunology and Vaccine Research, University of Connecticut Health Center, Farmington, CT 06030, USA.
Thomas A
TA
Stoklasek
Sara L
SL
Colpitts
Henry M
HM
Smilowitz
Leo
L
Lefrançois
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D064532:Histocompatibility Antigen H-2D; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D019409:Interleukin-15 / Q000502:physiology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000502:physiology*; D008231:Lymphopenia / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011940:Receptor Aggregation / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism* / Q000502:physiology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D001613:beta 2-Microglobulin