NK Cell Precursors in Human Bone Marrow in Health and Inflammation

Abstract

NK cells are generated from hematopoietic stem cells (HSC) residing in the bone marrow (BM), similar to other blood cells. Development toward mature NK cells occurs largely outside the BM through travel of CD34+ and other progenitor intermediates toward secondary lymphoid organs. The BM harbors multipotent CD34+ common lymphoid progenitors (CLPs) that generate T, B, NK, and Dendritic Cells and are devoid of erythroid, myeloid, and megakaryocytic potential. Over recent years, there has been a quest for single-lineage progenitors predominantly with the objective of manipulation and intervention in mind, which has led to the identification of unipotent NK cell progenitors devoid of other lymphoid lineage potential. Research efforts for the study of lymphopoiesis have almost exclusively concentrated on healthy donor tissues and on repopulation/transplant models. This has led to the widely accepted assumption that lymphopoiesis during disease states reflects the findings of these models. However, compelling evidences in animal models show that inflammation plays a fundamental role in the regulation of HSC maturation and release in the BM niches through several mechanisms including modulation of the CXCL12-CXCR4 expression. Indeed, recent findings during systemic inflammation in patients provide evidence that a so-far overlooked CLP exists in the BM (Lin − CD34 + DNAM-1 bright CXCR4 + ) and that it overwhelmingly exits the BM during systemic inflammation. These “inflammatory” precursors have a developmental trajectory toward surprisingly functional NK and T cells as reviewed here and mirror the steady state maintenance of the NK cell pool by CD34 + DNAM-1 − CXCR4 − precursors. Our understanding of NK cell precursor development may benefit from including a distinct “inflammatory” progenitor modeling of lymphoid precursors, allowing rapid deployment of specialized Lin − CD34 + DNAM-1 bright CXCR4 + -derived resources from the BM.

Understanding sepsis-induced immunosuppression and organ dysfunctions: from immunosuppression to immunotherapy

“…They protect the host from several microbial infections and tumors by limiting their spread and subsequent tissue damages. The functions of NK cells have not been fully understood in the consent of human disease due to their preferential location in tissues and low numbers in peripheral blood [40]. In sepsis, the levels of NK cells and their effector functions are markedly decreased.…”

Immunological Drivers in Graves' Disease: NK Cells as a Master Switcher

“…Additionally, based on the density of CD16 espression (a low-affinity receptor for the Fc portion of immunoglobulin G) and CD56 surface markers, NK cells could be further distinguished in two major subsets: CD56 bright CD16 dim/− and CD56 dim CD16 + cells ( 49 – 51 ). According to a well-supported theory, NK cell precursors leave the bone marrow, transit through peripheral blood and reach the lymph nodes, where, under the influence of cytokines produced by stromal matrix, they differentiate into CD56 + CD16 − ( 49 – 53 ). Maturation process is characterized by the down-regulation of CD56 and the acquisition of CD16 markers, as well as of “killer cell immunoglobulin-like receptors” (KIRs), getting the features of CD56 dim CD16 + cells ( 50 , 52 – 54 ).…”

“…According to a well-supported theory, NK cell precursors leave the bone marrow, transit through peripheral blood and reach the lymph nodes, where, under the influence of cytokines produced by stromal matrix, they differentiate into CD56 + CD16 − (49-53). Maturation process is characterized by the down-regulation of CD56 and the acquisition of CD16 markers, as well as of "killer cell immunoglobulin-like receptors" (KIRs), getting the features of CD56 dim CD16 + cells (50,(52)(53)(54). Therefore, CD56 dim CD16 + NKs show high potential of cytotoxicity, due to the high content of cytolytic granules (containing perforin and granzyme), the high expression of KIRs, ILT2 (immunologlobulin-like transcript 2), and CD16 itself (51,53).…”

“…Maturation process is characterized by the down-regulation of CD56 and the acquisition of CD16 markers, as well as of "killer cell immunoglobulin-like receptors" (KIRs), getting the features of CD56 dim CD16 + cells (50,(52)(53)(54). Therefore, CD56 dim CD16 + NKs show high potential of cytotoxicity, due to the high content of cytolytic granules (containing perforin and granzyme), the high expression of KIRs, ILT2 (immunologlobulin-like transcript 2), and CD16 itself (51,53). Conversely, CD56 bright CD16 dim/− are more immature cells, characterized by poor cytotoxic ability, high expression of inhibitory receptors (such as NKG2A), high ability to proliferate in response to IL-2 and elevated production of several cytokines, such as IFNγ, TNFα, granulocyte-macrophage colony-stimulating factor, IL-10 and IL-13, depending on the conditions of stimulation (51,(55)(56)(57)(58).…”

Recruited and Tissue-Resident Natural Killer Cells in the Lung During Infection and Cancer

“…NK cells (and other ILCs) derive from common lymphoid progenitor cells in the bone marrow. After differentiation to NK cell precursors, they leave the bone marrow in an immature state and then proceed through several stages of maturation and differentiation in secondary lymphoid tissues, from where they exit to the peripheral blood (5,6).…”