Abstract
CD4 Th cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. CD4 T cells differentiate into distinct Th effector or regulatory subsets in response to signals delivered to them during the course of infection. Ikaros is a transcription factor that is expressed in blood cells from the level of the hematopoietic stem cell. It is required for normal thymic T cell development and serves as a tumor suppressor, as lack of Ikaros in developing lymphoid cells results in leukemia. To study the role of Ikaros in CD4 T cell differentiation and function, an Ikaros conditional knockout mouse was developed such that Ikaros expression was deleted specifically in mature T cells, thus avoiding defects observed in germline Ikaros mutant mice. Using this model system, we have shown that in the absence of Ikaros, CD4 T cells are able to attain Th1, Th2, and Th17, but not inducible regulatory T, cell fates. However, they show enhanced expression of a cohort of proinflammatory cytokines, resulting in differentiation of Th17 cells with a phenotype that has been associated with autoimmunity and pathological inflammation. In addition, we define Ikaros as a repressor of the gene program associated with the response to type I IFNs, another key pathway whose deregulation is linked to autoimmunity. Taken together, these data definitively define Ikaros as a critical regulator at the center of the inflammatory response in T cells and highlight a potential role in suppressing autoimmunity.
This article is featured in In This Issue, p.1019
Footnotes
This work was supported by National Institutes of Health Grants AI113522 and AI133228 to S.W. P.A. was supported by an Immunology Training Program training grant funded by the National Institutes of Health (T32 A1007309).
The microarray data presented in this article have been submitted to the National Center for Biotechnology Information Expression Omnibus under accession number GSE119067.
Abbreviations used in this article:
- FDR
- false discovery rate
- GO
- gene ontology
- GSEA
- gene-set enrichment analysis
- HSC
- hematopoietic stem cell
- Ikflox
- Ikaros conditional knockout
- ISG
- IFN-stimulated gene
- iTreg
- inducible regulatory T
- KEGG
- Kyoto Encyclopedia of Genes and Genomes
- qRT-PCR
- quantitative real-time RT-PCR
- Treg
- regulatory T.
- Received September 18, 2018.
- Accepted December 10, 2018.
- Copyright © 2019 by The American Association of Immunologists, Inc.
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