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.
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.
Kolenko
V
V
Department of Immunology, Cleveland Clinic Foundation, OH 44195, USA.
Wang
Q
Q
Riedy
M C
MC
O'Shea
J
J
Ritz
J
J
Cathcart
M K
MK
Rayman
P
P
Tubbs
R
R
Edinger
M
M
Novick
A
A
Bukowski
R
R
Finke
J
J
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
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3