Defective differentiation of natural killer cells in SJL mice. Role of the thymus.

ABSTRACT

As previously shown, three distinct phenotypes exist in murine natural killer (NK) cell activity when it is evaluated by the endogenous levels of activity and the susceptibility to augmentation by interferon (IFN) and IFN inducers. The "low" phenotype has low levels of activity which can be poorly augmented by IFN, as in mice of SJL strain. The "inducible" phenotype exhibits low endogenous levels but can vigorously respond to IFN-mediated augmentation, as in A.SW strain. The "high" NK phenotype shows high levels of endogenous activity which can be augmented to still higher levels by IFN, as in B10.S mice. Since SJL mice with congenital absence of the thymus (nude) were of the inducible type, the effect of neonatal thymectomy was examined in the present study. Neonatal thymectomy was found to convert the low phenotype of SJL mice to the inducible, mimicking the effect of nu/nu genotype. Thymectomy as late as 25 days after birth was effective, but retransplantation of a syngeneic newborn or adult thymus, or thymocytes, failed to reverse the effect of thymectomy. The poor responsiveness of NK activity to IFN in SJL, therefore, is extrinsic to the NK cell lineage and is attributable to suppression or maturational block of NK cell differentiation by the thymus during the first few weeks of neonatal life. A series of experiments with bone marrow chimeras showed that the SJL recipients did not allow the expression of inducible or high phenotype by bone marrow progenitors from allogeneic donors with either phenotype. Therefore, the SJL recipients provide an environment which suppresses not only the development of IFN-sensitive NK cell precursors, but also the levels of endogenous NK cell activity. SJL bone marrow cells gave rise to NK activity of inducible phenotype in B10.S recipients, confirming the crucial role of the environment in which NK cell differentiation takes place.