CD56brightPerforinlow Noncytotoxic Human NK Cells Are Abundant in Both Healthy and Neoplastic Solid Tissues and Recirculate to Secondary Lymphoid Organs via Afferent Lymph

Abstract

As limited information is available regarding the distribution and trafficking of NK cells among solid organs, we have analyzed a wide array of tissues derived from different human compartments. NK cells were widely distributed in most solid tissues, although their amount varied significantly depending on the tissue/organ analyzed. Interestingly, the distribution appeared to be subset specific, as some tissues were preferentially populated by CD56brightperforinlow NK cells, with others by the CD56dimperforinhigh cytotoxic counterpart. Nevertheless, most tissues were highly enriched in CD56brightperforinlow cells, and the distribution of NK subsets appeared in accordance with tissue gene expression of chemotactic factors, for which receptors are differently represented in the two subsets. Remarkably, chemokine expression pattern of tissues was modified after neoplastic transformation. As a result, although the total amount of NK cells infiltrating the tissues did not significantly change upon malignant transformation, the relative proportion of NK subsets infiltrating the tissues was different, with a trend toward a tumor-infiltrating NK population enriched in noncytotoxic cells. Besides solid tissues, CD56brightperforinlow NK cells were also detected in seroma fluids, which represents an accrual of human afferent lymph, indicating that they may leave peripheral solid tissues and recirculate to secondary lymphoid organs via lymphatic vessels. Our results provide a comprehensive mapping of NK cells in human tissues, demonstrating that discrete NK subsets populate and recirculate through most human tissues and that organ-specific chemokine expression patterns might affect their distribution. In this context, chemokine switch upon neoplastic transformation might represent a novel mechanism of tumor immune escape.

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

“…In accordance with these findings, NK cells have been reported to be more abundant in PB than AL in a study involving non‐matched samples of PB and AL 23. Furthermore in humans, NK cells were found to be present at significantly lower levels in the AL compared with PB,16, 17 and recently NK cells were shown to be present in an accumulation of AL representing > 2% of lymphocytes 18. In the present study, bovine LNs contained the highest percentage of NK cells (6%; 3·03–11·7%; SD = 2·9) across the three compartments examined (Fig.…”

“…1d) support these findings whereby the percentage of CD2 − NK cells present within the PB was low, but was significantly increased in AL and LNs, suggesting preferential recruitment of the CD2 − subset of NK cells from the tissues to the draining LNs in steady‐state conditions. In studies of human afferent lymph, CD56 bright NK cells, which are equivalent to bovine CD2 − NK cells,30 were the main subset of NK cells present 18…”

“…It has been demonstrated in mice that NK cells migrate from the circulation to LNs via high endothelial venules 14, 15. NK cells are present in human afferent lymphatic vessels16, 17, 18 and one study has shown that NK cells are found in human efferent lymph (EL) 19…”

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

“…In agreement with this hypothesis we found that the amount of NCR þ ILC3 within tumour infiltrate correlated with the density of intratumoral TLS. Although other lymphocytes of the tumour microenvironment may produce a similar pattern of soluble factors, including LTa/b and TNF-a, which are critical for the possible LTi properties, NCR þ ILC3 may play an exclusive role in the tumour microenvironment: first, they might be directly activated by cancer cells via NKp44 and therefore represent an early innate source of relevant cytokines; then compared with intratumoral NK cells, which may also be directly activated by cancer cells 42,48 , NCR þ ILC3 apparently lack inhibitory receptors controlling their activities and can also provide a unique innate source of IL-2, a crucial growth factor for the clonal expansion of tumour-specific lymphocytes. On the other hand, the role of an innate source of IL-22 within tumour microenvironment remains to be identified and might even favour cancer cell growth 49 .…”

Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

“…Data obtained from murine experiments indicate that lymphoid tissues are the primary site for cellular interactions between NK cells and other immune cells (4)(5)(6). In humans, CD56 bright NK cells are enriched in marrow and spleen and make up the vast majority of mature NK cells in lymph node (18)(19)(20)(21)(22). Still, the mechanisms involved in the localization of human NK cells in lymphoid organs are largely unknown.…”