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The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells.

Clambey ET, Collins B, Young MH, Eberlein J, David A, Kappler JW, Marrack P - PLoS ONE (2013)

Bottom Line: While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism.Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells.These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.

View Article: PubMed Central - PubMed

Affiliation: Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. eric.clambey@ucdenver.edu

ABSTRACT
The Ikaros family of transcription factors is critical for normal T cell development while limiting malignant transformation. Mature CD8 T cells express multiple Ikaros family members, yet little is known about their function in this context. To test the functions of this gene family, we used retroviral transduction to express a naturally occurring, dominant negative (DN) isoform of Ikaros in activated CD8 T cells. Notably, expression of DN Ikaros profoundly enhanced the competitive advantage of activated CD8 T cells cultured in IL-12, such that by 6 days of culture, DN Ikaros-transduced cells were 100-fold more abundant than control cells. Expression of a DN isoform of Helios, a related Ikaros-family transcription factor, conferred a similar advantage to transduced cells in IL-12. While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism. Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells. These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.

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Gene expression profiles of Ikaros family members in mature CD8 T cells derived from Gene Expression Omnibus repository (GEO) datasets.(A) Gene expression profile of human CD8 T cell subsets, including naïve (TN), effector memory (TEM) or central memory CD8 T cells (TCM) with data from GSE23321. (B) Gene expression profile of mouse CD8 T cell subsets, including naïve, effector (Eff) or memory CD8 T cells (Mem) with data from GSE10239. Differential regulation of murine Ikzf1 and Ikzf2 gene expression in P14 cells after LCMV infection with data from GSE10239. Eff expression values are the combined average of array data from sorted Klrg1int or Klrg1hi-expressing P14 cells 4.5 days after LCMV Armstrong infection as in Methods. To allow comparison of microarray hybridization intensities across different samples, microarray data were normalized using standard normalization techniques, either the RMA16 (A) or RMA (B) algorithms to normalize two different generations of Affymetrix microarrays. For both human and mouse datasets, all Ikaros family members are significantly expressed above background (DABG p-values <0.05). Gene names refer to the following gene products: Ikzf1, Ikaros; Ikzf2, Helios; Ikzf3, Aiolos; Ikzf4, Eos; Ikzf5, Pegasus.
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pone-0057435-g001: Gene expression profiles of Ikaros family members in mature CD8 T cells derived from Gene Expression Omnibus repository (GEO) datasets.(A) Gene expression profile of human CD8 T cell subsets, including naïve (TN), effector memory (TEM) or central memory CD8 T cells (TCM) with data from GSE23321. (B) Gene expression profile of mouse CD8 T cell subsets, including naïve, effector (Eff) or memory CD8 T cells (Mem) with data from GSE10239. Differential regulation of murine Ikzf1 and Ikzf2 gene expression in P14 cells after LCMV infection with data from GSE10239. Eff expression values are the combined average of array data from sorted Klrg1int or Klrg1hi-expressing P14 cells 4.5 days after LCMV Armstrong infection as in Methods. To allow comparison of microarray hybridization intensities across different samples, microarray data were normalized using standard normalization techniques, either the RMA16 (A) or RMA (B) algorithms to normalize two different generations of Affymetrix microarrays. For both human and mouse datasets, all Ikaros family members are significantly expressed above background (DABG p-values <0.05). Gene names refer to the following gene products: Ikzf1, Ikaros; Ikzf2, Helios; Ikzf3, Aiolos; Ikzf4, Eos; Ikzf5, Pegasus.

Mentions: To date, there is limited information on Ikaros family members in CD8 T cells. During analysis of published microarray analyses of mouse and human CD8 T cells, however, we noted that all five Ikaros members are expressed at a detectable level, with expression in naïve, effector and memory CD8 T cells in both human and mouse (Fig. 1A,B). In addition, in both humans and mice, there is a trend towards reciprocal regulation of Ikaros (Ikzf1) and Helios (Ikzf2), with Helios mRNA modestly increased in effector or effector memory cells relative to either naive or memory CD8 T cells (Fig. 1A–B). While future studies will be required to investigate Ikaros family mRNA splicing and protein expression in CD8 T cells, these data demonstrate that mature CD8 T cells express Ikaros family members, and suggest that the Ikaros family may influence CD8 T cell function.


The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells.

Clambey ET, Collins B, Young MH, Eberlein J, David A, Kappler JW, Marrack P - PLoS ONE (2013)

Gene expression profiles of Ikaros family members in mature CD8 T cells derived from Gene Expression Omnibus repository (GEO) datasets.(A) Gene expression profile of human CD8 T cell subsets, including naïve (TN), effector memory (TEM) or central memory CD8 T cells (TCM) with data from GSE23321. (B) Gene expression profile of mouse CD8 T cell subsets, including naïve, effector (Eff) or memory CD8 T cells (Mem) with data from GSE10239. Differential regulation of murine Ikzf1 and Ikzf2 gene expression in P14 cells after LCMV infection with data from GSE10239. Eff expression values are the combined average of array data from sorted Klrg1int or Klrg1hi-expressing P14 cells 4.5 days after LCMV Armstrong infection as in Methods. To allow comparison of microarray hybridization intensities across different samples, microarray data were normalized using standard normalization techniques, either the RMA16 (A) or RMA (B) algorithms to normalize two different generations of Affymetrix microarrays. For both human and mouse datasets, all Ikaros family members are significantly expressed above background (DABG p-values <0.05). Gene names refer to the following gene products: Ikzf1, Ikaros; Ikzf2, Helios; Ikzf3, Aiolos; Ikzf4, Eos; Ikzf5, Pegasus.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585008&req=5

pone-0057435-g001: Gene expression profiles of Ikaros family members in mature CD8 T cells derived from Gene Expression Omnibus repository (GEO) datasets.(A) Gene expression profile of human CD8 T cell subsets, including naïve (TN), effector memory (TEM) or central memory CD8 T cells (TCM) with data from GSE23321. (B) Gene expression profile of mouse CD8 T cell subsets, including naïve, effector (Eff) or memory CD8 T cells (Mem) with data from GSE10239. Differential regulation of murine Ikzf1 and Ikzf2 gene expression in P14 cells after LCMV infection with data from GSE10239. Eff expression values are the combined average of array data from sorted Klrg1int or Klrg1hi-expressing P14 cells 4.5 days after LCMV Armstrong infection as in Methods. To allow comparison of microarray hybridization intensities across different samples, microarray data were normalized using standard normalization techniques, either the RMA16 (A) or RMA (B) algorithms to normalize two different generations of Affymetrix microarrays. For both human and mouse datasets, all Ikaros family members are significantly expressed above background (DABG p-values <0.05). Gene names refer to the following gene products: Ikzf1, Ikaros; Ikzf2, Helios; Ikzf3, Aiolos; Ikzf4, Eos; Ikzf5, Pegasus.
Mentions: To date, there is limited information on Ikaros family members in CD8 T cells. During analysis of published microarray analyses of mouse and human CD8 T cells, however, we noted that all five Ikaros members are expressed at a detectable level, with expression in naïve, effector and memory CD8 T cells in both human and mouse (Fig. 1A,B). In addition, in both humans and mice, there is a trend towards reciprocal regulation of Ikaros (Ikzf1) and Helios (Ikzf2), with Helios mRNA modestly increased in effector or effector memory cells relative to either naive or memory CD8 T cells (Fig. 1A–B). While future studies will be required to investigate Ikaros family mRNA splicing and protein expression in CD8 T cells, these data demonstrate that mature CD8 T cells express Ikaros family members, and suggest that the Ikaros family may influence CD8 T cell function.

Bottom Line: While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism.Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells.These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.

View Article: PubMed Central - PubMed

Affiliation: Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. eric.clambey@ucdenver.edu

ABSTRACT
The Ikaros family of transcription factors is critical for normal T cell development while limiting malignant transformation. Mature CD8 T cells express multiple Ikaros family members, yet little is known about their function in this context. To test the functions of this gene family, we used retroviral transduction to express a naturally occurring, dominant negative (DN) isoform of Ikaros in activated CD8 T cells. Notably, expression of DN Ikaros profoundly enhanced the competitive advantage of activated CD8 T cells cultured in IL-12, such that by 6 days of culture, DN Ikaros-transduced cells were 100-fold more abundant than control cells. Expression of a DN isoform of Helios, a related Ikaros-family transcription factor, conferred a similar advantage to transduced cells in IL-12. While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism. Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells. These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.

Show MeSH
Related in: MedlinePlus