Human neutrophil heterogeneity exists, but is it meaningful?

By John I. Gallin N EUTROPHILS are one of the major phagocytes of the body’s defenses, and they have long been considered a homogeneous cell population that seeks and destroys pathogens and then mysteriously disappears into oblivion. In recent years, it has become clear that the concept of neutrophil homogeneity is not valid, and peripheral blood neutrophils have been shown to be heterogeneous by several parameters (Table 1 ). The purpose of this review is to summarize the evidence for neutrophil heterogeneity and to speculate on the potential importance of this heterogeneity in in vitro investigations and in the homeostasis of host defenses. Observations of neutrophil heterogeneity can be traced back to the I 920s, when Florence Sabin described poor locomotory capacity in immature neutrophils (myelocytes).’ Sabin speculated that the sluggishness of immature cells kept them within the bone marrow. Thus, although heterogeneity of neutrophil locomotion had been recognized for many years, it was felt to reflect variances in cell maturity, rather than different populations of cells. In the I 920s, McCutcheon, who was the first to quantitate individual neutrophil locomotion, noted wide variability in rates of locomotion.2 Subsequently, others have confirmed McCutchen’s observations and have showed that mdividual neutrophils may vary up to tenfold in their rates of locomotion.3 This variability was not felt to reflect differences in cell maturity, at least as judged by light microscopic assessment. Recently, in a careful study of individual cells obtained from clot preparations, Howard concluded that neutrophils could be classified as moving slowly ( 7.O m/min) or fast ( 7.O zm/ mm).6 The heterogeneity was felt to be due to endogenous differences within the cells.6 Harvath and Leonard have separated neutrophils into two populations that differ in chemotactic responsiveness.7 N umerous other observations suggest heterogeneity of neutrophils. For example, every clinician who has looked at a Gram stain of infected sputum, as in Fig. lA, has probably been aware of the possibility of neutrophil heterogeneity. Infected sputum, even in the setting of overwhelming pneumonia, usually has bactena associated with only some neutrophils. What are the nonphagocytosing, mature-appeari ng neutrophils doing? In vitro observations provide similar evidence suggesting heterogeneous phagocytosis, as about 20% of adherent neutrophils won’t ingest opsonized microorganisms in vitro (Fig. 1 B). These observations have all prompted more intensive studies, which have further expanded the concept of neutrophil heterogeneity.