Rapid generation of a functional NK-cell compartment

Abstract

Bone marrow transplants are an important therapeutic tool for treating certain types of cancer as well as genetic diseases affecting the hematopoietic system. Until the transferred stem cells differentiate and reconstitute the immune system, recipients are at increased risk from opportunistic infections. We report the rapid generation of a functional natural killer (NK) compartment in lethally irradiated mice that received bone marrow cells from a syngeneic donor by treatment with IL-2/anti-IL-2 antibody complexes. We demonstrate that IL-2 complexes specifically expand the donor but not the host NK population and discuss the implications of this finding in the context of graft-versus-host disease and tumor relapse. Finally, we show that NK cells rapidly generated by IL-2 complexes kill MHC class I-deficient cells effectively in vivo. These data underline the unique therapeutic potential of IL-2 complexes.

Figure 1

Rapid restoration of NK-cell numbers and function following irradiation and marrow grafting by IL-2 complex treatment. Irradiated bone marrow recipient mice (BMC mice) and (nonirradiated) B6 control mice were treated with IL-2 complex (IL-2C) on day 2 and day 4 after bone marrow transfer. (A) Spleen cells were analyzed on day 8 after bone marrow transfer and percentage of donor and host-derived cells, displayed in the histogram, was determined through congenic markers. (B) BrdU (2 mg) was injected intraperitoneally on day 5 after bone marrow transplantation, following treatment with IL-2 complex on day 2 and day 4. Animals were killed 10 hours after BrdU injection, and BrdU incorporation by NK1.1⁺CD3⁻ cells in the spleen was determined. (C) A mix of CFSE-low B6 and CFSE-high β2M^−/− splenocytes was transferred into control or B6 BMC mice and NK-mediated in vivo killing determined 48 hours later.

Figure 2

IL-2 complex rapidly expands the NK compartment from immature precursors in IL-15^−/− mice. (A) B6 or IL-15^−/− mice received injections of IL-2 complex or IL-15 on day 0 and day 2 and spleens were analyzed on day 3. (B) Mice received congenically marked, NK1.1⁺CD3⁻-enriched splenocytes on day 0 and IL-2 complex injections on day 0 and day 2. Proliferation was measured by CFSE dilution on day 3.