BM can represent a location suitable for self-renewal and persistence of NK cell population with enhanced functional capacity. phenotype and function of NK cells as well as their requirements for bone marrow maintenance and/or homing. mechanisms compensating deficiency that include increased proliferation of tissue resident cells (11). Recently, a peculiar ILC precursor has been described in human peripheral blood, which can give rise to mature cytotoxic Atopaxar hydrobromide NK cells and ILC subsets (12). These findings, along with the presence of cells having progenitor phenotypes in several peripheral tissues, imply the existence of homeostatic mechanisms of BM egress for ILC precursors. Thus, one of the paradigms in the ILC field is based on the capacity of ILC precursors to leave the BM and complete their differentiation programs in the tissues. This behavior mainly discriminates helper ILCs, which develop (17, 18). NK cell differentiation and maturation have been traditionally thought to occur exclusively in the bone marrow (BM), but evidence in humans and mice suggests that precursor and immature NK Atopaxar hydrobromide cells can also migrate in secondary lymphoid tissues (SLT) to complete maturation (19). Human NK cells develop from hematopoietic stem cells (HSCs) and during transition from CD56high into CD56low, they undergo a progressive loss of NKG2A and expression of KIRs, CD57, and NKG2C on terminally differentiated NK cells (20C22). Moreover, a new Lin?CD34+DNAM-1brightCXCR4+ CLP precursor has been found in the peripheral blood of patients with chronic inflammatory conditions. The phenotype of these cells suggests that they originate from the BM as they still retain the CXCR4 and DNAM-1 receptors, and that they are released from endosteal niches due to bone remodeling occurring during chronic inflammation (23). Mouse NK cells develop from HSCs encompassing four developmentally related subsets that can be distinguished based on expression levels of the integrin chain CD11b and of a member of the TNF receptor superfamily, CD27. The bone marrow is not only a place for development and maturation, but BM NK cells perform important functions for defense against infections and tumors linked to their ability to traffick and/or reside in this organ (24C28). NK Cells and Other ILC Populations in the Bone Marrow Several members of the chemokine family influence NK/ILC tissue localization by regulating their release from IgG2a Isotype Control antibody (APC) the BM as well as their tissue homing and retention. Beside this type of conventional NK cells that can be found in circulation, tissue resident NK cells present specific characteristics that involve for example CD69, possibly linked to suppression of sphingosine 1-phosphate receptor-1 expression which retains immune cells in lymph nodes and tissues. Another mechanism is the engagement of chemokine receptors, like for example CXCR6 and CCR5, that are highly expressed on tissue-resident NK cells Atopaxar hydrobromide in human lymphoid tissues and liver, while peripheral blood-derived NK cells can be recognized by expression of CCR7 (29). NK cell subsets display a differential pattern of chemokine receptor expression. In humans, CD56high NK cells are targeted to lymph nodes CCR7, preferentially express CXCR3 and have higher CXCR4 expression levels as compared with CD56low cells. CXCR1, ChemR23, and CX3CR1 are expressed only by CD56low NK cells. ILC subsets have differential tissue tropism, reflecting their transcriptional and functional states. Transcriptomic analyses established in the context of the Immgen project have revealed Atopaxar hydrobromide both specific and overlapping expression patterns for chemokine receptors in mouse ILCs (30). CXCR3 is one of the chemokine receptors showing subset specificity. This receptor is typically associated to the type 1 response and in general with T-BET expressing ILCs, including NK cells, ILC1 and a subset of ILC3 expressing NCRs. The chemokine receptors CCR4 and CCR8 are associated, instead, with the type 2 response and are specifically expressed on ILC2. Finally, CCR6 and CXCR5 are found mainly on lymphoid tissue inducer (LTi)-like cells (30C33). Examples of chemokine receptors widely express on ILCs include CXCR4 and CXCR6. Upon maturation, mouse NK cells start to express sphingosine 1-phosphate receptor.