Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.

María Soledad Caldirola,Norberto Walter Zwirner,María Guadalupe Rodríguez Broggi,Liliana Bezrodnik,María Isabel Gaillard

doi:10.3389/fimmu.2018.01429

Abstract

Natural killer (NK) cells play a pivotal role during immunity against viruses and circumstantial evidence also indicates that they can protect the host against developing tumors. Peripheral blood NK cells comprise CD56brightCD16lo/− cells that constitutively express CD25 (IL-2Rα) and CD56dimCD16hi cells that express CD25 upon activation. Using NK cells from two patients, one with a primary immunodeficiency characterized by a homozygous mutation in CD25 (born in year 2007 and studied since she was 3 years old) and one with a homozygous mutation in STAT5b (born in year 1992 and studied since she was 10 years old), we observed that the absence of IL-2 signaling through CD25 promotes the accumulation of CD56brightCD16high NK cells, and that CD56brightCD16lo, CD56brightCD16high, and CD56dimCD16high NK cells of this patient exhibited higher content of perforin and granzyme B, and proliferation capacity, compared to healthy donors. Also, CD56bright and CD56dim NK cells of this patient exhibited a reduced IFN-γ production in response to cytokine stimulation and increased degranulation against K562 cells. Also, the CD25-deficient patient presented a lower frequency of terminally differentiated NK cells in the CD56dimCD16hi NK subpopulation compared to the HD (assessed by CD57 and CD94 expression). Remarkably, CD56dimCD16high NK cells from both patients exhibited notoriously higher expression of CD62L compared to HD, suggesting that in the absence of IL-2 signaling through CD25 and STAT5b, NK cells fail to properly downregulate CD62L during their transition from CD56brightCD16lo/− to CD56dimCD16hi cells. Thus, we provide the first demonstration about the in vivo requirement of the integrity of the IL-2/CD25/STAT5b axis for proper human NK cell maturation.

Highlights

Natural killer (NK) cells are essential players in immunity against viral infections [1,2,3]
The CD25-deficient systematically exhibited NK cell counts within the range of the healthy population (221 ± 41 NK cells/mm3) since she was 3 years old, while the STAT5b-deficient patient exhibited low NK cell counts sporadically since she was 10 years old (Figure 1A)
While NK cells from the healthy donors (HDs) progressively downregulated CD62L along maturation stages, such downregulation was not observed in NK cells from the CD25-deficient and from the STAT5b-deficient patient, as even CD56dimCD16hi NK cells from both displayed high amounts of CD62L. These results suggest that the absence of adequate IL-2 signaling impedes the downregulation of CD62L that is usually a feature observed during the transition of CD56brightCD16lo/− to CD56dimCD16hi NK cells

Summary

Introduction

Natural killer (NK) cells are essential players in immunity against viral infections [1,2,3]. A prospective cohort study demonstrated that high cytotoxic activity of NK cells is associated with a decreased risk of cancer [4]. They display a high degree of diversity that determines their tissue tropism and responses to external insults [5, 6]. Two major populations of NK cells can be detected in peripheral blood, based on the expression of CD56 and CD16 (FcRγIIIa): about a 90% are CD56dimCD16hi, while the rest exhibit a CD56brightCD16lo/− phenotype. NK cells can be divided into developmental stages based on the expression of CD27 and CD11b [14,15,16,17,18]

Methods

Results

Conclusion