Immunosurveillance by Hematopoietic Progenitor Cells Trafficking through Blood, Lymph, and Peripheral Tissues

Abstract

Constitutive egress of bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) into the blood is a well-established phenomenon, but the ultimate fate and functional relevance of circulating HSPCs is largely unknown. We show that mouse thoracic duct (TD) lymph contains HSPCs that possess short- and long-term multilineage reconstitution capacity. TD-derived HSPCs originate in the BM, enter the blood, and traffic to multiple peripheral organs, where they reside for at least 36 hr before entering draining lymphatics to return to the blood and, eventually, the BM. HSPC egress from extramedullary tissues into lymph depends on sphingosine-1-phosphate receptors. Migratory HSPCs proliferate within extramedullary tissues and give rise to tissue-resident myeloid cells, preferentially dendritic cells. HSPC differentiation is amplified upon exposure to Toll-like receptor agonists. Thus, HSPCs can survey peripheral organs and can foster the local production of tissue-resident innate immune cells under both steady-state conditions and in response to inflammatory signals.

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

“…Although some of the NK cells in SLO might be CD56 bright recirculating from the blood, others could represent early maturation stages of NK cells developing from hematopoietic precursor cells that repopulate extramedullary tissues and retain multi-lineage reconstitution capacity [16]. Caligiuri's group has identified lymphocytes in tonsils and lymph nodes representative of distinct stages of NK-cell development that differentiated into NK cells expressing high levels of CD56 [17][18][19].…”

Stromal Cell-Derived CXCL12 and CCL8 Cooperate To Support Increased Development of Regulatory Dendritic Cells Following Leishmania Infection

“…Although different DC subpopulations arise mainly from variably committed DC precursors that are selectively recruited from BM to the peripheral tissue (15)(16)(17)(18), tissue-specific differentiation of DCs provides complementary routes for establishing DC heterogeneity in diverse tissues (9,44,45). In the steady state, this model of DC differentiation would involve tissue-resident HSPCs and/or their descendents; during inflammation, this might be supplemented by the recruitment of additional HSPCs.…”

“…In the steady state, this model of DC differentiation would involve tissue-resident HSPCs and/or their descendents; during inflammation, this might be supplemented by the recruitment of additional HSPCs. In addition, HSPC differentiation can be amplified upon exposure to TLR agonists (9). Thus, the local microenvironment has multiple opportunities for shaping the DC repertoire.…”

“…Although these data suggest an important role for CXCR4/CXCL12 in BM retention of HSPCs, the relative contribution to progenitor retention by other stromal cell-derived chemokines is poorly defined. Furthermore, under homeostatic conditions, HSPCs in the BM are not entirely sessile but contain a population of highly migratory cells, and some HSPCs recirculate constantly between BM and blood (9). Blood HSPC numbers can be dramatically modified during inflammation and following stimulation by several cytokines, including CSF-2 and CSF-3 (10,11).…”

“…Differentiation of DCs mainly proceeds from HSPCs within the BM, and several developmental intermediates of DCs have been isolated from blood and various tissues (15)(16)(17)(18). In a previous study, it was reported that migratory HSPCs also proliferate and differentiate within extramedullary tissues and give rise to tissueresident DCs (9). As a heterogeneous population, DCs contribute to the functional differentiation of effector and regulatory T cells; therefore, DCs play a dual role in inducing adaptive immune responses to foreign Ags and in maintaining tolerance to self (19,20).…”