IL-15 trans-presentation promotes human NK cell development and differentiation in vivo

By Nicholas D. Huntington, N. Legrand, N. Alves, Barbara Jaron, K. Weijer, A. Plet, Erwan Corcuff, Erwan Mortier, Y. Jacques, H. Spits and 1 more. Journal of Experimental Medicine, 2009

596 citations recorded by the source corpus.

The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self–major histocompatability complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2−/−γc−/− mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor α (IL-15Rα) significantly augmented human NK cells. IL-15–IL-15Rα complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16+KIR+ NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56hiCD16−KIR− to CD56loCD16+KIR−, and finally to CD56loCD16+KIR+. These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15–responsive cells during immunotherapy strategies.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/10e4603189afd231acbdbbff162b8d554cf40bb6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. J. P. Santo
2. M. Jakóbisiak
3. Witold Lasek
4. R. Zagożdżon
5. H. Spits
6. Dan R. Littman
7. K. Honda

In Oncology

1. M. Jakóbisiak
2. Witold Lasek
3. R. Zagożdżon

Citations in the corpus

• Interleukin 12: still a promising candidate for tumor immunotherapy? (2014, background): “IL-15 is a key regulator of NK cell development, activation, proliferation and survival [10–12,90,91,103], and accelerates their reconstitution following bone marrow transplantation [104].”
• The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling (2011, result): “That idea has been confirmed by studies of mice carrying a human immune system, which have shown that the human IL-15–IL-15Rα complex promotes the development of human NK cell”