IL-2, IL-7, and IL-15: Multistage regulators of CD4+ T helper cell differentiation  Kaitlin A. Read, Michael D. Powell, Paul W. McDonald, Kenneth J. Oestreich  Experimental Hematology  Volume 44, Issue 9, Pages 799-808 (September 2016) DOI: 10.1016/j.exphem.2016.06.003 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 IL-2 signaling differentially regulates T helper cell development. In response to IL-2 signaling, T helper cells upregulate IL-12Rβ2, IL-2Rα, IL-2Rβ, and IL-4Rα (in green). Depending on additional cytokines present in the environment, the cell is then capable of upregulating several subset-specific gene expression programs. (i) IL-2 and IL-12 signaling result in the upregulation of T-bet and Blimp-1 expression and the generation of TH1 cells, which are responsible for mounting responses to intracellular pathogens. (ii) IL-2 and TGF-β signaling results in increased expression of Foxp3 and the development of TREG cells, the central mediators of immune tolerance. (iii) IL-2 and IL-4 signaling promotes the induction of Gata3 expression and the development of TH2 cells, which assist in clearance of extracellular parasites. Conversely, IL-2 signaling results in the repression of gp130, IL-6Rα, and IL-7Rα (in red). As a consequence, TH17, TFH, and TMEM cell formation are inhibited by IL-2 signaling. In the case of TFH and TMEM populations, this inhibition is likely due to decreases in cytokine receptor expression and the STAT5-dependent repression of the transcription factor Bcl-6, which is critical for the development of both cell types. Similarly, IL-2 represses the expression of IL-6R complexes and inhibits TH17 cell development. Experimental Hematology 2016 44, 799-808DOI: (10.1016/j.exphem.2016.06.003) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 IL-2, IL-7, and IL-15 repress Bcl-6 expression through STAT5-dependent mechanisms. (i) IL-2 signaling in TH1 cells leads to STAT5 activation and translocation to the nucleus, where it binds to the Bcl6 locus and represses Bcl-6 expression. This repression is likely due to the displacement of STAT3 at the same site, which is responsible in part for Bcl6 activation. As a result, IL-2 signaling represses Bcl-6-dependent TFH and TCM gene programs and maintains the effector TH1 cell state. (ii) IL-7 signaling similarly represses Bcl-6 expression via a STAT5-dependent mechanism, perhaps allowing for increased cell survival, proliferation, and metabolic function. IL-7 signaling may also function to promote memory T cell trafficking to the T cell zones of secondary lymphoid organs. (iii) Trans-presentation of IL-15 represses Bcl-6 expression, likely via a STAT5-mediated pathway (dotted line). Similar to IL-7, IL-15-dependent repression of Bcl-6 may allow for increased cell survival, proliferation, and alterations to cellular metabolism. Experimental Hematology 2016 44, 799-808DOI: (10.1016/j.exphem.2016.06.003) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions