Continuous CD27 triggering in vivo strongly reduces NK cell numbers

Abstract

NK cells are important mediators of the early defense. In mice, immature and mature NK (mNK) cells constitutively express the TNF receptor family member CD27; however, mNK cells eventually lose CD27 expression and become resting NK cells. Interaction of CD27 with its ligand, CD70, enhances proliferation and effector functions of NK cells. We used mice that constitutively express CD70 on B cells (CD70-Tg) to study the in vivo effects of continuous triggering of CD27 on NK cells. Continuous CD70-CD27 interaction resulted in strongly down-modulated CD27 expression on NK cells and gradually reduced absolute NK cell numbers. This reduction was most prominent in the mNK cell subpopulation and was at least partially due to increased apoptosis. Residual NK cells showed lower expression of activating Ly49 receptors and normal (liver) or decreased (spleen) IFN-c production. Nevertheless, NK cells from CD70-Tg mice displayed higher YAC-1 killing capacities. CD70-Tg NK cells exhibited up-regulated expression of NKG2D, which is in accordance with the increased YAC-1 lysis, as this is mainly NKG2D-dependent. Taken together, this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells. On a single cell basis, however, residual NK cells display enhanced cytotoxicity.Key words: CD70-Tg mice . Cytotoxicity . Differentiation Supporting Information available online Introduction NK cells are large granular lymphocytes of the innate immune system that play a crucial role in the early host defense [1,2]. Upon activation, they directly eliminate target cells through exocytosis of perforin-and granzyme-containing granules, or by Fas ligand (CD178) or TRAIL pathways [3][4][5][6][7]. NK cells also produce cytokines and chemokines, which enable them to recruit non-specific haematopoetic cells, activate dendritic cells and prime adaptive lymphocytes [8][9][10][11]. As such, NK cells bridge between innate and adaptive immunity. The functional behaviour of NK cells is regulated by the engagement of a broad array of activating and inhibitory cell membrane receptors (reviewed in Lanier [12]).The BM is considered to be the main site for NK cell development [13][14][15][16]. Here, multipotent haematopoietic precursors generate NK cell precursors (NKP). Murine NKP are lineage(lin) À CD122 1 NK1.1 À CD49b À . NKP differentiate into immature NK (iNK) cells, which exhibit a lin À CD122 1 NK1. [20,21]. Interestingly, Hayakawa and Smyth [22]showed that within the TCR b À NK1.1 1 gated NK cell pool there is a CD11b low subpopulation, including both iNK and early mNK cells, which is homogenously CD27 high (referred to as subset 1), whereas the CD11b high population of late mNK cells consists of two functionally distinct subsets: i.e. CD27 high (referred to as subset 2) and CD27 low (referred to as subset 3). NK cells from subset 1 are the first NK cell population detected after BM transplantation and they give rise to subset 2 after adoptive transfer. Subset 2 consists of fu...

Plasmid Vector-Linked Maturation of Natural Killer (NK) Cells Is Coupled to Antigen-Dependent NK Cell Activation during DNA-Based Immunization in Mice

“…These features made it difficult to determine whether or not both effector functions were performed by the same NK cell subset. This is consistent with the results of De Colvenaer et al, who reported that continuous CD27 triggering in vivo resulted in strongly downmodulated CD27 expression on NK cells and in a severe reduction in NK cell numbers (12). Our results that showed downregulation of CD27 expression on NK cells and a decrease in NK cell percentages after DNA-based immunization indirectly confirm their activation state.…”

Eosinophil differentiation in the bone marrow is inhibited by T cell–derived IFN-γ

“…20 NK cell numbers are strongly reduced in these mice, and the remaining NK cells produce less IFN-␥ than wild-type (WT) mice. 21 Here we describe that CD27-mediated T-cell activation has a strong and specific impact on myelopoiesis, as CD70TG mice are almost devoid of eosinophils, whereas the formation of neutrophils and monocytes is actually increased. Detailed analysis revealed that this defect in eosinophil formation can be fully attributed to the increased production of IFN-␥ by effector T cells in these mice.…”

Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis

“…10 Consequently, these CD70-transgenic (CD70TG) mice display improved T-cell immunity and efficiently counter a challenge with influenza virus or tumor cells. 11 However, the increased pool of effector T cells also seriously disrupts the hematopoietic system at different levels, as CD70TG mice gradually lose their B cells 10 and eosinophilic granulocytes 12 because of chronic exposure to IFN-␥, lose their NK cells, 13 and eventually even exhaust their naive T-cell pool. 14 Here we describe that CD70TG mice also become anemic, which is fully dependent on the production of IFN-␥.…”