Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2019-02, Vol.202 (4), p.1112-1123
Main Authors: Lyon de Ana, Carolina, Arakcheeva, Ksenia, Agnihotri, Parul, Derosia, Nicole, Winandy, Susan
Format: Article
Language:English
Subjects:
Animals
CD4-Positive T-Lymphocytes - immunology
Female
Ikaros Transcription Factor - deficiency
Ikaros Transcription Factor - genetics
Ikaros Transcription Factor - immunology
Inflammation - genetics
Inflammation - immunology
Interferon Type I - immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1801270