Lineage(-)Sca1+c-Kit(-)CD25+ cells are IL-33-responsive type 2 innate cells in the mouse bone marrow

J Immunol. 2011 Dec 1;187(11):5795-804. doi: 10.4049/jimmunol.1102242. Epub 2011 Nov 2.

Abstract

IL-33 promotes type 2 immune responses, both protective and pathogenic. Recently, targets of IL-33, including several newly discovered type 2 innate cells, have been characterized in the periphery. In this study, we report that bone marrow cells from wild-type C57BL/6 mice responded with IL-5 and IL-13 production when cultured with IL-33. IL-33 cultures of bone marrow cells from Rag1 KO and Kit(W-sh/W-sh) mice also responded similarly; hence, eliminating the possible contributions of T, B, and mast cells. Rather, intracellular staining revealed that the IL-5- and IL-13-positive cells display a marker profile consistent with the Lineage(-)Sca-1(+)c-Kit(-)CD25(+) (LSK(-)CD25(+)) cells, a bone marrow cell population of previously unknown function. Freshly isolated LSK(-)CD25(+) cells uniformly express ST2, the IL-33 receptor. In addition, culture of sorted LSK(-)CD25(+) cells showed that they indeed produce IL-5 and IL-13 when cultured with IL-33 plus IL-2 and IL-33 plus IL-7. Furthermore, i.p. injections of IL-33 or IL-25 into mice induced LSK(-)CD25(+) cells to expand, in both size and frequency, and to upregulate ST2 and α(4)β(7) integrin, a mucosal homing marker. Thus, we identify the enigmatic bone marrow LSK(-)CD25(+) cells as IL-33 responsive, both in vitro and in vivo, with attributes similar to other type 2 innate cells described in peripheral tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / immunology
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Cell Lineage / immunology*
  • Cell Separation
  • Cytokines / biosynthesis
  • Flow Cytometry
  • Immunity, Innate / immunology*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-33
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Male
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-kit / immunology

Substances

  • Antigens, Ly
  • Cytokines
  • Il2ra protein, mouse
  • Il33 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-33
  • Interleukins
  • Ly6a protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins c-kit