The role of the CD28/B7 interaction in the regulation of NK cell responses during infection with Toxoplasma gondii.
We examined the role of the CD28/B7 interaction in regulation of NK cell activity. Cells transfected with B7 enhanced IL-12-induced production of IFN-gamma by IL-2-activated, CD28+ NK cells, but not by resting CD28- NK cells. The ability of B7 transfectants to enhance NK cell production of IFN-gamma was dependent on the intracellular adhesion molecule-1/LFA-1 interaction and could be inhibited by TGF-beta, but not IL-10. Since IL-12-induced production of IFN-gamma by NK cells is associated with resistance to certain infections, we examined whether the CD28/B7 interaction regulated NK cell responses during infection. Infection of SCID mice with Toxoplasma gondii resulted in the appearance of a population of CD28+ NK cells, NK cell production of IFN-gamma, and increased NK cell cytolytic activity. Administration of CTLA4-Ig to SCID mice infected with T. gondii inhibited these latter two effects and resulted in a significant increase in parasite burden. The stimulus for CD28 expression by NK cells in SCID mice infected with T. gondii appeared to be independent of IL-2. However, mRNA for IL-15, a cytokine with properties similar to those of IL-2, was detected in tissues of SCID mice infected with T. gondii. In vitro experiments demonstrated that IL-15 could stimulate resting NK cells to express functionally active CD28 as well as enhance the production of IFN-gamma by SCID splenocytes stimulated with T. gondii. Together our data demonstrate that the interaction of CD28+ NK cells with B7 regulates NK cell production of IFN-gamma associated with resistance to infection and that IL-15 may be involved in these events.
Hunter
C A
CA
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Ellis-Neyer
L
L
Gabriel
K E
KE
Kennedy
M K
MK
Grabstein
K H
KH
Linsley
P S
PS
Remington
J S
JS
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D018106:CD28 Antigens / Q000096:biosynthesis / Q000502:physiology*; D060908:CTLA-4 Antigen; D005260:Female; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D012515:Mast-Cell Sarcoma; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D019409:Interleukin-15; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D018664:Interleukin-12; D000069594:Abatacept; D007371:Interferon-gamma