Cutting Edge: Salivary Gland NK Cells Develop Independently of Nfil3 in Steady-State

Abstract

Nfil3 is viewed as an obligate transcription factor for NK cell development. However, mouse CMV (MCMV) infection recently was shown to bypass the requirement for Nfil3 by inducing the appearance of NK cells that express the MCMV-specific receptor Ly49H. Thus, signals transmitted by Ly49H and proinflammatory cytokines are sufficient to promote NK cell differentiation in the absence of Nfil3. In this study, we report that salivary gland (SG) NK cells develop in an Nfil3-independent fashion in the steady-state in the absence of MCMV or any infection. Moreover, we show that SG NK cells have an integrin profile reminiscent of tissue-resident lymphocytes and express TRAIL for killing target cells. These results demonstrate that SG NK cells, although related to conventional NK cells, are a distinct subset of innate lymphoid cells that deviates from the conventional developmental pathway, perhaps under the influence of tissue-specific factors.

NK cells and type 1 innate lymphoid cells: partners in host defense

“…r e v i e w npg 7 6 0 VOLUME 17 NUMBER 7 JULY 2016 nature immunology r e v i e w population, found in salivary glands, is similar to the liver-resident ILC1s in that it expresses CD49a and kills target cells using TRAIL 35 ; but, in contrast to liver ILC1s, these cells express Eomes and CD49b, which are both expressed by NK cells, and they produce very low levels of IFN-γ 35 The first studies reporting human ILC1s described two different populations of IFN-γ-producing ILC1s 40,41 . One expressed high amounts of CD127 and CD161 but lacked CD56, CD94, granzyme B and perforin, which are expressed by mature NK cells 40 .…”

PLZF expression maps the early stages of ILC1 lineage development

“…However, several recent studies have revealed the existence of distinct subpopulations of NK-like cells that, unlike the recirculating classical NK (cNK) cells found in spleen, blood, and lymph nodes, exhibited the unusual property of long-term residence in particular tissues, including liver, intestinal epithelium, uterus, skin, and salivary glands (4)(5)(6)(7)(8)(9). For example, in parabiotic pairs of CD45-congenic mice, a fraction of CD3e − NK1.1 + liver cells were found to be tissue-resident rather than recirculating cells (6).…”

Natural Killer Cell Reduction and Uteroplacental Vasculopathy

“…However, there is clear evidence that subtypes of NK cells reside in tissues (tissue-resident NK cells) such as liver, thymus, uterus, 40 and the salivary gland 41 exhibiting different functions and capabilities. Strikingly, tissue-resident NK cells do not seem to require the NK cell specification transcription factor Nfil3 (nuclear factor interleukin-3-regulated Figure 5.…”

“…F, There was no difference in the uteroplacental unit/fetal weight ratio after anti-asialo GM1 therapy in SD rats (0.19±0.00 vs 0.18±0.01 in the SD control rabbit serum group; P=0.1, unpaired t test with Welch correction, shown mean with SEM); n=49 fetuses out of n=6 anti-asialo GM1-treated, SD mother rats and n=43 fetuses out of n=5 normal, rabbit serum-treated, SD mother rats. *P<0.01. protein), 41 leading to the assumption that tissue-resident NK cells are distinct from circulating NK cells and could represent a different cell lineage. 40 The independence of Nfil3 has been shown for uNK cell differentiation in mice as well.…”