Human fetal lymphoid tissue–inducer cells are interleukin 17–producing precursors to RORC+ CD127+ natural killer–like cells

Abstract

The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue-inducer cells (LTi cells) as lineage-negative RORC+ CD127+ cells with the functional ability to interact with mesenchymal cells through lymphotoxin and tumor necrosis factor. Human LTi cells were committed natural killer (NK) cell precursors that produced interleukin 17 (IL-17) and IL-22. In vitro, LTi cells gave rise to RORC+ CD127+ NK cells that retained the ability to produce IL-17 and IL-22. Postnatally, similar populations of LTi cell-like cells and RORC+ CD127+ NK cells were present in tonsils, and both secreted IL-17 and IL-22 but no interferon-gamma. Our data indicate that lymph node organogenesis is controlled by an NK cell precursor population with adaptive immune features and demonstrate a previously unappreciated link between the innate and adaptive immune systems.

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

“…They do show, however, that the level of expression of c-kit and CD127, two receptors often used as markers to define distinct NK-cell lineages [37,38] or different NK-cell subsets [4,9,12,15,17,19] may simply reflect the cytokine level of the environment they have been isolated from and that caution should be taken to interpret low c-kit-or CD127-levels as proof of maturation of CD56 bright toward CD56 dim .…”

“…4, lower panel). The latter is another strong indication that ptCD56 bright are in vivo cytokine-activated CD56 bright rather than immature precursors.Impact of addition or withdrawal of cytokines on CCR7, c-kit and CD127 expression by CD56 bright , ptCD56 bright and NK CCR7, c-kit and CD127 are markers used to define distinct NKcell lineages [37,38] or different NK-cell subsets [4,9,12,15,17,19]. Approximately, half of the CD56 bright in normal peripheral blood are CCR7 1 , whereas virtually all ptCD56 bright are negative (Fig.…”

Innate Lymphoid Cells in Graft-Versus-Host Disease

“…Group 3 ILC are characterized by IL‐22 and IL‐17 secretion in response to IL‐23 and IL‐1β stimulation 5, 23, 24. ILC3 express the transcription factor RORγt, and the development of mouse ILC3 depends on RORγt, Notch, and Tcf1, as recently summarized elsewhere 6.…”

NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures

“…Notably, ILC subpopulations produce an array of cytokines that in variety match those of T-helper cell subsets. Besides conventional NK (cNK) cells, an additional ILC population expressing NCRs, but functionally different from NK cells, has been identified in both humans [18][19][20][21][22] and mice [23][24][25] . Unlike NK cells, in humans this NCR þ cell population is dependent on the orphan nuclear receptor (ROR)gt transcription factor and on the interleukin (IL)-7Ra for its development and function.…”

“…Notably, post-natal CD56 þ RORgt þ CD127 þ cells from human tonsils have been shown to express high levels of NKp44 and NKp46 (ref. 31), to produce lymphotoxin-a and to exert LT-inducing ability, at least in vitro 19,31 .…”