Decades following the discovery of natural killer (NK) cells, their developmental pathways in mice and humans have not yet been completely deciphered. secondary lymphoid tissues (SLTs), including tonsils and lymph nodes. Here, we provide an update of recent progress that has been made with regard to human NK cell development in SLTs, and we discuss these new findings in the context of contemporary models of ILC development. monokine stimulation (3). While the developmental relationship between these human NK cell subsets has not been definitively established, evidence suggests that CD56bright NK cells represent immediate physiologic precursors of CD56dim NK cells (19, 24C29). Alternative hypotheses include that CD56bright NK cells represent activated NK cells and/or that PB NK cell subsets derive from distinct hematopoietic progenitor cells (HPCs) and developmental pathways (22, 30C33). Recent published data from Dunbar and colleagues claim that the second option will be the case in rhesus macaques (34). Human being NK Cell Advancement in SLTs Human being NK cells had been originally considered to develop firmly inside the bone tissue marrow (BM) (3, 35). The observation supported This idea that Lin?CD56+ cytotoxic NK cells could be generated subsequent culture BML-277 of purified human being BM Compact disc34+ HPCs with either BM-derived stroma or with IL-15, which may be made by stroma (36, 37). non-etheless, more recent intensive characterization of HPCs and putative downstream NK cell developmental intermediates (NKDIs) reveals how the second option are normally enriched in SLTs, including tonsils, spleen, and LNs, recommending that in human beings NK cells may also, otherwise preferentially, develop in SLTs (Shape ?(Shape1A)1A) (38C42). Identical NKDIs have already been determined within the thymus also, liver organ, and uterus (43C45). Therefore, human being NK cell advancement is likely not really limited to SLTs (46). Open up in another window Shape 1 patterns of surface area antigen manifestation support a style of human being organic killer (NK) cell advancement in supplementary lymphoid cells (SLTs). (A) immunophenotypic analyses of CD3+ cells (top row, left plots), CD19+ cells (top row, right plots), and Lin?CD56+ cells (bottom row) in the indicated tissues demonstrate how immature T, B, and NK cell developmental intermediates (designated by the red circles and ovals) are naturally enriched in the thymus, bone marrow, and SLTs, respectively. Of note, the SLT populations BML-277 designated by the red circles in the bottom row also likely contain some ILC3s, which can express CD56 (14). The red arrows in the bottom row highlight the relative enrichment of stage 4b CD56brightNKp80+CD16? NK cells in SLTs. (B) Immunophenotypic analysis of Lin? ILCs in human tonsil demonstrating the two-way patterns of CD34, CD117, CD94, NKp80, and CD16 expression as they relate to one another. The red arrows depict the putative directions of progressive NK cell development in SLTs. (C) Schematic representation of the proposed stages of human NK cell development in SLTs. The stages are defined according to the differential expression of CD34, CD117, interleukin (IL)-1R1, CD94, NKp80, CD16, and CD57, and the red lines underline the surface antigen changes that define each stage transition. Although not depicted, it is noted that CD56 expression is first detected at stage 2b (heterogeneous), peaks at stage 4b (CD56bright), and then decreases to the level of most peripheral blood NK cells at stage 6 (CD56dim). Also not depicted is killer immunoglobulin-like receptor BML-277 expression, which is first detected within stage 4b in SLTs (40). In 2006, five putative stages of human SLT NK cell development were described according to the differential expression of CD34, CD117, CD94, and CD16 (41, 47, 48). Stage 1 cells (Lin?CD34+CD117?CD94?CD16?) lack expression of the common FOXO4 IL-2/IL-15 receptor beta chain (IL-2/15R, CD122) and are thus not responsive to exogenous soluble IL-2 or IL-15 in the presence of exogenous soluble IL-15 in media without other cytokines or support cells (41). Stage 2 cells also constitutively express a functional high affinity IL-2 receptor, including the IL-2R subunit (CD25), and can differentiate in response to picomolar concentrations of IL-2 (39). The physiologic relevance of the cytokine receptor manifestation is not however known and is not tested (39). When examined in mass polyclonal ethnicities under supportive circumstances originally, stage 1 and stage 2 cells had been multipotent and may bring about T cells and DCs in addition to to NK cells, although they cannot generate B cells or myeloid cells (41). On the other hand, human being stage 3 cells (Lin?Compact disc34?Compact disc117+Compact disc94?CD16?) lacked T DC and cell developmental potential. Stage 3 cells could, nevertheless, bring about mature NK cells and and had been therefore originally suggested to represent dedicated NK cell precursors (41). Stage 3 cells are specific from mature NK cells for the reason that they absence high manifestation of T-BET and EOMES, cannot make IFN-, and so are not capable of mediating.