title: Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas.
abstract: The proliferative capacity of T cells infiltrating human tumors is known to be impaired, possibly through their interaction with tumor. Here we demonstrate that soluble products derived from renal cell carcinoma (RCC-S) explants but not normal kidney can inhibit an IL-2-dependent signaling pathway that is critical to T cell proliferation. A major target of the immunosuppression was the IL-2R-associated protein tyrosine kinase, Janus kinase 3 (Jak3). RCC-S suppressed basal expression of Jak3 and its increase following stimulation with anti-CD3/IL-2. Jak3 was most sensitive to suppression by RCC-S; however, reduction in expression of p56(lck), p59(fyn), and ZAP-70 was observed in some experiments. Expression of other signaling elements linked to the IL-2R (Jak1) and the TCR (TCR-zeta, CD3-epsilon, and phospholipase C-gamma) were minimally affected. In naive T cells, RCC-S also partially blocked induction of IL-2R alpha-, beta- and gamma-chain expression when stimulating via the TCR/CD3 complex with anti-CD3 Ab. To determine whether RCC-S suppressed IL-2-dependent signaling, primed T cells were employed since RCC-S had no effect on IL-2R expression but did down-regulate Jak3 expression and, to a lesser degree, p56(lck) and p59(fyn). Reduction in Jak3 correlated with impaired IL-2-dependent proliferation and signal transduction. This included loss of Jak1 kinase tyrosine phosphorylation and no induction of the proto-oncogene, c-Myc. These findings suggest that soluble products from tumors may suppress T cell proliferation through a mechanism that involves down-regulation of Jak3 expression and inhibition of IL-2-dependent signaling pathways.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, OH 44195, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kolenko
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: M C
authors.initials: MC
authors.lastname: Riedy
authors.forename: J
authors.initials: J
authors.lastname: O'Shea
authors.forename: J
authors.initials: J
authors.lastname: Ritz
authors.forename: M K
authors.initials: MK
authors.lastname: Cathcart
authors.forename: P
authors.initials: P
authors.lastname: Rayman
authors.forename: R
authors.initials: R
authors.lastname: Tubbs
authors.forename: M
authors.initials: M
authors.lastname: Edinger
authors.forename: A
authors.initials: A
authors.lastname: Novick
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
authors.forename: J
authors.initials: J
authors.lastname: Finke
mesh_terms: D002292:Carcinoma, Renal Cell / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D053616:Janus Kinase 3; D007680:Kidney Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D000090063:Proto-Oncogene Mas; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3