Do Natural Killer Cells Engage in Regulated Reactions Against Self to Ensure Homeostasis?

Abstract

Host reactivities not requiring immunization in the mouse, especially natural resistance of irradiated animals to accept grafts of normal or malignant hemopoietic cells, were compared with NK activity against the YAC-1 lymphoma. The effects of several independent variables known to influence natural resistance in vivo had a similar effect on the NK system. Figure 12 lists an impressive array of shared properties and positive correlations. In contrast, the distinctions were few and minor. Many of the positive correlations were of particular significance since the experimental variables either have opposing or no effects on conventional induced immunity. The multiplicity and pervasiveness of these correlations suggest that the cellular mechanisms underlying natural reactivities are similar or common. Cytotoxic effectors mediating natural resistance to normal cells, tumors, and cells infected with intracellular pathogens may be distinct in terms of target selectivity, yet belong to a single cell lineage subject to common regulatory influences for differentiation and function. Regulation of reactivity via suppressor cells was studied in the NK system only. The spleens of mice selected for low levels of NK activity (resulting from young age, irradiation, and treatment with the macrophage-active agents l-carrageenan or hydrocortisone acetate) contained cells capable of inhibiting the lytic function of NK effectors taken from untreated adult donors. All the suppressor cells studied were thymus-independent, as judged by their occurrence in spleens of genetically athymic mice; the suppressive function was resistant to 2000 rads of gamma-rays administered in vitro and was not restricted by the major histocompatibility complex, without exception. However, two major classes of suppressors were identified: (a) macrophagelike cells inducible by l-carrageenan or hydrocortisone acetate, and (b) nonadherent cells found in spleens of untreated infants and of irradiated adult mice. It is proposed that the suppression of NK cytolysis demonstrated in vitro was a manifestation of regulatory mechanisms modulating the level of NK activity in vivo. Macrophagelike cells that are induced, activated, or inactivated by bacteria, viruses, hormones, and other agents may act as regulators of differentiation, maturation, and function of cells belonging to the NK lineage. Nonadherent cells could be either a distinct class of suppressors or immature NK cells capable of binding but not lysing target cells. In the latter case, regulation would be achieved via competitive binding of targets by pre-NK cells presumably in dynamic equilibrium with functional (i.e. matured) NK effectors.

Protective Mechanisms against Pulmonary Infection with Influenza Virus. I. Relative Contribution of Polymorphonuclear Leukocytes and of Alveolar Macrophages to Protection during the Early Phase of Intranasal Infection

“…This evidence strongly suggests that PMN are the cells mainly responsible for the protection in the early phase against influenza virus infection. It has been reported that NK cells are also sensitive to carrageenan but resistant to X-irradiation (Kiessling et al, 1977;Cudkowicz & Hochman, 1979) and that NK cells participate in non-specific resistance in several virus infections (Bukowski et al, 1983;Habu et al, 1984). In our studies, however, intraperitoneal administration of carrageenan before intranasal infection with the high dose of influenza virus did not increase virus titre in the lung at the early phase of infection (Fig.…”

Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen.

“…Suppression was also reduced in glucose-free medium, which did not support the generation of RO. by natural killer cells can be stimulated by interferon (11) or interleukin-2 (12), and in the mouse, can be suppressed by a variety of agents including strontium-89 (13), carrageenans (14), silica particles (14), Co-rynebacterium parvum (15), estrogens (16), hydrocortisone (17), and prostaglandins (18). Certain of these agents appear to induce cellular suppression of natural killing (NK)', but the suppressor cells have been difficult to characterize, and the mechanism of suppression is unknown (15,17,19). The regulation of NK is of particular interest because of evidence that NK may be important in host defense against malignancy; the growth of certain tumors in vivo is inversely correlated with levels of NK, and spontaneous malignancy is increased when NK is deficient (20)(21)(22).…”

Development of thymocytes in organ culture: Migrant cells with natural killer cell characteristics

“…The data, however, add to the thesis that NK cells may have a role in thymopoiesis. Cells with NK-like characteristics have been implicated in controlling cell growth and differentiation in haemopoiesis (25) and B cell differentiation (26). It might be expected that NK cells are involved in the control of haemopoiesis as all haemopoietic cells have similarities in their regulation (27).…”