Natural killer (NK) cell activity in mice with acute graft-versus-host reactions: characterization of a Thy-1+ NK-like cell with a broadened spectrum of lytic activity in the spleen and lymph nodes.
We have shown that acute (GVH) reactions produced in the parental-F1 hybrid combination, A/J----(C57BL/6 x A/J)F1 result in the activation of two cytotoxic cell populations: a host-derived Thy-1+/- natural killer (NK) cell with a lytic spectrum confined to YAC-1 targets, and a donor-derived Thy-1+ NK-like cell that has the ability to lyse target cells that are normally insensitive to lysis by NK cells. Cold-target inhibition (CTI) experiments have shown that the greater range of target cell killing seen in the NK-like population is mediated by a single effector cell with a broadened lytic repertoire. Percoll density fractionation studies have revealed that NK and NK-like cells co-fractionate, suggesting that both are large granular lymphocytes. We we have also shown that NK-like cells do not express either Lyt-2 or L3T4 markers. We have also observed that there is a close temporal relationship between elevated levels of interleukin-2 (IL-2) secretion by spleen cell cultures from mice with GVH disease and the subsequent emergence of splenic NK activity in both acute [A/J----(C57BL/6 x A/J)F1] and chronic (A/J----CBA x A/J)F1 GVH reactions. We have also noted that, despite high levels of IL-2 secretion, mice with chronic GVH reactions do not generate NK-like activity. Interferon (IFN) measurements have shown that, although increased IFN activity can be detected in both acute and chronic models, a preponderance of IFN-alpha/beta and some IFN-gamma is produced in the acute reaction, whereas only IFN-gamma can be detected in the chronic model. These results suggest that, although IL-2 may participate in augmenting conventional NK activity, IL-2 by itself does not generate NK-like activity. We suggest that IFN-alpha/beta may be the cytokine that, either alone or in concert with IL-2, triggers the NK-like cell response. The NK-like cell described in our study resembles a phenotypically identical, donor-derived large granular lymphocyte, identified by others, in close proximity to dead or dying epithelial cells in mice with GVH disease [14]. It has been suggested that these cells may mediate tissue injury. If in fact these graft-derived NK-like cells are involved in the pathogenesis of acute GVH disease, our present findings suggest that they must first be activated by an appropriate complement of cytokines that includes IFN-alpha/beta.(ABSTRACT TRUNCATED AT 400 WORDS)
MacDonald
G C
GC
Department of Pathology, University of Manitoba, Faculty of Medicine, Winnepeg, Canada.
Gartner
J G
JG
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis*; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D005260:Female; D005677:G(M1) Ganglioside; D006028:Glycosphingolipids / Q000276:immunology; D006087:Graft vs Host Reaction; D007372:Interferons / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D013154:Spleen / Q000276:immunology*; D018800:Thy-1 Antigens
D000954:Antigens, Surface; D006028:Glycosphingolipids; D007376:Interleukin-2; D018800:Thy-1 Antigens; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D007372:Interferons