Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation

• Published in: Blood Vol. 116; no. 14; pp. 2494 - 2503
• Main Authors: Castillo, Eliseo F., Acero, Luis F., Stonier, Spencer W., Zhou, Dapeng, Schluns, Kimberly S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 07.10.2010; Americain Society of Hematology; American Society of Hematology
• Series: Immunobiology
• Subjects: Animals; Biological and medical sciences; Cell Proliferation; Dendritic Cells - immunology; Gene Deletion; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - immunology; Immunobiology; Interferon-gamma - immunology; Interleukin-15 - immunology; Interleukin-15 Receptor alpha Subunit - genetics; Interleukin-15 Receptor alpha Subunit - immunology; Liver - immunology; Medical sciences; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - cytology; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Proto-Oncogene Proteins c-bcl-2 - immunology; Thymus Gland - cytology; Thymus Gland - immunology; Cell maturation; Invariant natural killer T cell; Thymus gland; Hematology; Cytokine; Transpresentation; Microenvironment; Interleukin 15
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-03-277103

Invariant NKT (iNKT) cells are an innate type of T cells, which respond rapidly on activation. iNKT cells acquire these innate-like abilities during development; however, the signals driving development and functional maturation remain only partially understood. Because interleukin-15 (IL-15) is crucial for iNKT development and is delivered by transpresentation, we set out to identify the cell types providing IL-15 to developing iNKT cells and determine their role at the various states of development and maturation. We report here that transpresentation of IL-15 by parenchymal cells was crucial for generating normal number of iNKTs in the thymus, whereas both hematopoietic and parenchymal cells regulated iNKT cell numbers in the periphery, particularly in the liver. Specifically, dendritic cells contributed to peripheral iNKT cell numbers by up-regulating Bcl-2 expression and promoting extrathymic iNKT cell ex-pansion and their homeostatic proliferation. Whether IL-15 affects functional maturation of iNKT cells was also examined. In IL-15Rα−/− mice, CD44HighNK1.1+ iNKT cells displayed decreased T-bet expression and in response to α-galactosylceramide, had deficient interferon-γ expression. Such defects could be reversed by exogenous IL-15 signals. Overall, these studies identify stage-specific functions of IL-15, which are determined by the tissue microenvironment and elucidate the importance of IL-15 in functional maturation.