title: Transforming growth factor-beta expression and natural killer cell responses during virus infection of normal, nude, and SCID mice.
abstract: The experiments presented here assess the contribution of T cells to NK cell regulation and transforming growth factor-beta (TGF-beta) production. The kinetics of NK cell activation in the absence of T cells was evaluated by comparing responses in athymic nude and SCID mice to those in normal C3H/HeN, C57BL/6, and BALB/c mice during lymphocytic choriomeningitis virus (LCMV) infection. T cell-deficient mice exhibited high NK cell activity for longer periods of time post-infection. To determine whether the reduction in NK cell activation at later times post-infection of normal mice resulted from induction of negative regulatory elements, mice were treated with the chemical IFN and NK cell inducing agent polyinosinic-polycytidylic acid (poly I:C). Although poly I:C induced plasma IFN in both uninfected and LCMV-infected normal mice, NK cell activity was elevated in the uninfected mice only. In vivo expression of TGF-beta protein in normal and T cell-deficient mice was evaluated by immunohistochemical studies on splenic sections. TGF-beta proteins were not detected in sections from uninfected mice but were induced in all strains during infection. High levels of TGF-beta proteins were localized to discrete cells, and diffuse staining was observed along marginal zones. The ability of the splenic leukocytes to release TGF-beta into conditioned media was evaluated in the Mv 1 Lu biologic assay. Transient acid treatment to release active factor from the latent form and use of specific neutralizing antibodies demonstrated that leukocytes from all strains of infected mice had released latent TGF-beta 1 into conditioned media. However, cells from infected nude or SCID mice produced substantially less active TGF-beta than those isolated from normal mice. Production of biologically active TGF-beta 1 was dependent upon the presence of T cells in normal mice, as in vivo depletion of CD4+ and CD8+ T cells by antibody treatment resulted in augmented NK cell activity and loss of active factor production. The lack of TGF-beta production was accompanied by increased NK cell numbers; at late times post-infection, T cell-deficient C57BL/6-nude mice had almost twice as many NK1.1+CD3- cells per spleen compared with T cell-containing C57BL/6 littermate control mice. Treatment with active TGF-beta 1 reduced the numbers of NK cells per spleen in infected nude mice to the levels found in infected littermate controls.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: H C
authors.initials: HC
authors.lastname: Su
authors.forename: R
authors.initials: R
authors.lastname: Ishikawa
authors.forename: C A
authors.initials: CA
authors.lastname: Biron
mesh_terms: D000818:Animals; D007694:Killer Cells, Natural / Q000502:physiology*; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D011070:Poly I-C / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
chemical_list: D016212:Transforming Growth Factor beta; D011070:Poly I-C