Roles for Common Cytokine Receptor γ-Chain-Dependent Cytokines in the Generation, Differentiation, and Maturation of NK Cell Precursors and Peripheral NK Cells in Vivo

Abstract

NK cells differentiate in adult mice from bone marrow hemopoietic progenitors. Cytokines, including those that signal via receptors using the common cytokine receptor γ-chain (γc), have been implicated at various stages of NK cell development. We have previously described committed NK cell precursors (NKPs), which have the capacity to generate NK cells, but not B, T, erythroid, or myeloid cells, after in vitro culture or transfer to a fetal thymic microenvironment. NKPs express the CD122 Ag (β chain of the receptors for IL-2/IL-15), but lack other mature NK markers, including NK1.1, CD49b (DX5), or members of the Ly49 gene family. In this report, we have analyzed the roles for γc-dependent cytokines in the generation of bone marrow NKP and in their subsequent differentiation to mature NK cells in vivo. Normal numbers of NKPs are found in γc-deficient mice, suggesting that NK cell commitment is not dependent on IL-2, IL-4, IL-7, IL-9, IL-15, or IL-21. Although IL-2, IL-4, and IL-7 have been reported to influence NK cell differentiation, we find that mice deficient in any or all of these cytokines have normal NK cell numbers, phenotype, and effector functions. In contrast, IL-15 plays a dominant role in early NK cell differentiation by maintaining normal numbers of immature and mature NK cells in the bone marrow and spleen. Surprisingly, the few residual NK cells generated in absence of IL-15 appear relatively mature, expressing a variety of Ly49 receptors and demonstrating lytic and cytokine production capacity.

T and B lymphocytes exert distinct effects on the homeostasis of NK cells

“…In addition, we examined the expression of CD43 (sialoadhesin) and CD11b (integrin aM), which serve as markers of functional NK cell maturation [8,33]. However, T and/or B cell deficiency had no significant effect on the acquisition of CD43 and CD11b by BM or spleen NK cells (data not shown).…”

γc cytokines provide multiple homeostatic signals to naive CD4+ T cells

“…During lymphoid development, distinct cytokines have been identified that promote the survival and proliferation of B, T and NK cell precursors in the bone marrow and in the thymus. For example, IL-7 and stem cell factor are crucial for early thymocyte differentiation, IL-7 and fetal liver kinase-2 ligand drive B cell development, and IL-15 is essential for the generation of immature NK cells [1][2][3][4][5]. These observations indicate that cytokines have specific (i.e.…”

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

“…CD3 À CD122 þ immature NKPs are the earliest known progenitors committed to become NK cells, defined by the absence of mature markers such as NK1.1, NKG2D, NKG2A/C/E, Ly49, CD49b and CD11b. 31,33 Our results show that the lack of p85a resulted in the reduction of CD3 À CD122 þ NK1.1 À CD49b À progenitors in the BM and spleen. Similar reductions were also observed in (Figures 2c and d).…”

“…49 Also, expression of CD122 by early progenitors uniquely marks the committed NKPs. 33 Both the initiation of CD122 expression and its level in p85a À/À NK cells were not affected, indicating that p85a is dispensable for this developmental step. Also, percentages of CD3 À CD122 þ cells were not altered in p85a À/À mice.…”