International Immunology Advance Access originally published online on January 15, 2009
International Immunology 2009 21(3):203-216; doi:10.1093/intimm/dxn140
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
IL-7 and the HIV Tat protein act synergistically to down-regulate CD127 expression on CD8 T cells
1 Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada
2 Department Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada
3 Division of Infectious Diseases, Ottawa Hospital General Campus, 501 Smyth Road, Ottawa, Ontario, Canada
Correspondence to: P. MacPherson; E-mail: pmacpherson{at}ottawahospital.on.ca
IL-7 signaling is essential for optimal CD8 T cell function, homeostasis and establishment of memory. We have previously shown decreased expression of the IL-7 receptor 
-chain (CD127) on CD8 T cells from HIV-infected patients with active viral replication. We have also shown that soluble HIV Tat protein specifically down-regulates CD127 on the surface of CD8 T cells and impairs cell proliferation and cytolytic potential following stimulation with IL-7 in vitro. We now show that soluble HIV Tat protein and IL-7 at near physiologic concentrations act synergistically to suppress CD127 expression. While soluble HIV Tat protein and IL-7 both independently reduce CD127 expression on the surface of CD8 T cells, Tat concentrations of 10 µg ml–1 and IL-7 concentrations of 500 pg ml–1 are required in vitro to have an appreciable effect. However, where 0.5 µg ml–1 of Tat has no effect on CD127 expression and 200 pg ml–1 of IL-7 decreases CD127 by only 14%, these two together at these same concentrations induce a 35% reduction in CD127 expression after 24 h. Inhibition of Janus kinase (JAK) completely blocks IL-7's ability to down-regulate CD127 on the surface of CD8 T cells and also abolishes synergy with Tat. Interestingly, while Tat acts synergistically with IL-7 to reduce CD127 expression, it antagonizes IL-7-induced cell proliferation and Ki-67 expression and has no effect on IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation or expression of the anti-apoptotic gene Bcl-2. Thus, by affecting different IL-7 signal transduction pathways, HIV Tat protein is able to impair both CD8 T cell activation and proliferation without inducing apoptosis.
Keywords: CTL, IL-7 receptor, JAK
Transmitting editor: Andras Falus
Received 15 August 2008, accepted 8 December 2008.