Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation

Abstract

Natural killer (NK) cells fulfill essential accessory functions for the priming of antigen-specific cytotoxic T lymphocytes (CTLs). On the basis of a NKG2D-ligandpositive tumor model, we obtained results implicating NK-mediated regulatory as well as NK-mediated cytolytic activities in the initiation and persistence of CTL activity. Indeed, CD8 ؉ T-cell-dependent tumor rejection requires NK cell function in vivo, because tumors will progress both on depletion of NK cells or in the absence of optimal NK activity. Here we provide evidence that the absence of NK cells during subcutaneous tumor growth will abrogate generation of antitumor CTL responses and that this process can be linked to the expansion of alternatively activated monocytes. Indeed, our in vitro studies demonstrate that in splenic cultures from NK-deficient tumor-bearing mice, lack of type 1-associated cytokines correlates with the presence of type 2 (alternatively activated) monocytes and the production of type 2 cytokines. Furthermore, these type 2 monocyte-containing splenic adherent populations potently suppress subsequent memory CTL restimulation. We evaluated the role of NK lytic effector functions in the efficient switch of the immune system toward classical (type 1) activation by including differentially activated monocytic populations as targets in cytotoxicity assays. The results indicate that the accessory function of NK cells depends partially on the ability of activated NK cells to preferentially engage type 2 antigen-presenting cells. Thus, when the immune system tends to be type 2 oriented, NK cells can drive an efficient type 2 3 type 1 switch in the population of antigen-presenting cells to provide signaling for the generation of

Pattern recognition receptors and differentiation antigens define murine myeloid cell heterogeneity ex vivo

“…A marked increase in the number of Gr-1 + CD11b + splenocytes has been previously observed in this model [33]. Gating on CD11b high splenocytes in a similar way to Fig.…”

“…Mice with naturally progressing tumors [33] were identified after 20 days and were assayed for an expansion of CD11b + Gr-1 + myeloid cells as reported [33].…”

NK Cells Negatively Regulate Antigen Presentation and Tumor-Specific CTLs in a Syngeneic Lymphoma Model

“…Other studies also showed that expression of NKG2D ligands resulted in NK cell-dependent resistance to tumor cell challenge (33). A s.c. NKG2D ligandpositive lymphoma model in AKR mice demonstrated a stimulatory role for NK cells in CTL generation (34). Depletion of NK cells in this AKR tumor model led to alternatively activated macrophage formation and subsequent suppression of CTL generation.…”

Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells

“…Our results further showed that the activated NK cell population is one critical factor in controlling this process in BW-Sp3 tumor bearers. Indeed, in the absence of fully activated NK cells, upon depletion or in tumor progressors (where NK activity is severely reduced), Ag-specific CTL activity is impaired and can be correlated with the presence of M2 and myeloid suppressive cells (70). Tumor-secreted GM-CSF was another factor proposed to be involved in the induction of myeloid suppressors (37,71).…”