NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors

  1. Anton, Olga M. 2
  2. Vielkind, Susina 2
  3. Peterson, Mary E. 2
  4. Tagaya, Yutaka 1
  5. Long, Eric O. 2
  1. 1 †Division of Basic Science and Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201
  2. 2 *Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and
Revista:
The Journal of Immunology

ISSN: 0022-1767,  1550-6606

Año de publicación: 2015

Volumen: 195

Número: 10

Páginas: 4810-4821

Tipo: Artículo

DOI: 10.4049/JIMMUNOL.1500414 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: The Journal of Immunology

Resumen

IL-15 bound to the IL-15Rα–chain (IL-15Rα) is presented in trans to cells bearing the IL-2Rβ–chain and common γ-chain. As IL-15 transpresentation occurs in the context of cell-to-cell contacts, it has the potential for regulation by and of other receptor–ligand interactions. In this study, human NK cells were tested for the sensitivity of IL-15 transpresentation to inhibitory receptors. Human cells expressing HLA class I ligands for inhibitory receptors KIR2DL1, KIR2DL2/3, or CD94-NKG2A were transfected with IL-15Rα. Proliferation of primary NK cells in response to transpresented IL-15 was reduced by engagement of either KIR2DL1 or KIR2DL2/3 by cognate HLA-C ligands. Inhibitory KIR–HLA-C interactions did not reduce the proliferation induced by soluble IL-15. Therefore, transpresentation of IL-15 is subject to downregulation by MHC class I–specific inhibitory receptors. Similarly, proliferation of the NKG2A+ cell line NKL induced by IL-15 transpresentation was inhibited by HLA-E. Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. IL-15Rα was not excluded from, but was evenly distributed across, inhibitory synapses. These findings demonstrate a novel mechanism to attenuate IL-15–dependent NK cell proliferation and suggest that inhibitory NK cell receptors contribute to NK cell homeostasis.

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