Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells.
During infection, naïve CD4(+) T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well-established role in the regulation of natural killer and CD8(+) T cell immune responses. However, the effect of IL-15 signaling on CD4(+) T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through trans-presentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated TH1 cells are responsive to trans-presented IL-15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the TH1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a TFH-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD4(+) T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches.
Virginia Tech Carilion Research Institute, Roanoke, VA; USA.|Virginia Tech Carilion School of Medicine, Roanoke, VA; USA.
Ian D
ID
Cooley
Virginia Tech Carilion Research Institute, Roanoke, VA; USA.
Kaitlin A
KA
Read
Virginia Tech Carilion Research Institute, Roanoke, VA; USA.|Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA; USA.|Virginia Tech Carilion School of Medicine, Roanoke, VA; USA.
Kenneth J
KJ
Oestreich
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1