Regulation of CD40L expression on natural killer cells by interleukin-12 and interferon gamma: its role in the elicitation of an effective antitumor immune response.
Effector cell functions are regulated by a number of positive signals for the mediation of antitumor immunity. The CD40 and CD40 ligand (CD40L) interaction has been implicated in the generation of effective cell-mediated and humoral immune responses, where cytokines have been shown to play a significant role in the expression of these molecules. Our earlier studies have shown that spontaneous regression of a rat histiocytoma transplanted s.c. is mediated by CD8 + CD3- NK cells. The CD40-CD40L mediation during tumor regression was of interest. Tumor-transplanted animals showed enhanced expression of CD40L on natural killer (NK) and T cells, when compared to cells from normal animals. CD40 expression on AK-5 tumor cells was also induced after s.c. transplantation. Administration of anti-(interleukin-12) (anti-IL-12) and anti-(interferon gamma) (anti-IFNgamma) antibodies in tumor-bearing animals showed down-regulation of the expression of CD40L on NK and T cells with simultaneous inhibition of cytotoxic acitivity of NK cells, cytokine release and the production of antitumor antibody. Naive NK cells, when co-cultured with fixed AK-5 cells, were induced to express CD40L. CD40L expression modulated the immune response exerted by NK cells, in part by the activation of nuclear factor kB (NF-kB). Furthermore, the signaling via CD40L through the use of anti-CD40L antibody promoted the in vitro activation of cytotoxic as well as NF-kappaB binding activity in NK cells from tumor-transplanted animals. These observations demonstrate that the expression of CD40L by the effector cells is regulated by IL-12 and IFNgamma, and could effectively modulate the NK-cell-mediated immune response during the regression of AK-5 tumor.
Jyothi
M D
MD
Centre for Cellular and Molecular Biology, Hyderabad, India.
Khar
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics; D018920:Coculture Techniques; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018219:Histiocytoma, Benign Fibrous / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016328:NF-kappa B; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma