Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells

John P Ray; Heather D Marshall; Brian J Laidlaw; Matthew M Staron; Susan M Kaech; Joe Craft

doi:10.1016/j.immuni.2014.02.005

Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells

Immunity. 2014 Mar 20;40(3):367-77. doi: 10.1016/j.immuni.2014.02.005. Epub 2014 Mar 13.

Authors

John P Ray¹, Heather D Marshall¹, Brian J Laidlaw¹, Matthew M Staron¹, Susan M Kaech², Joe Craft³

Affiliations

¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
² Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789, USA.
³ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].

Abstract

Follicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4(+) T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of IFN-inducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper 1 (Th1) cell-like effector phenotype. Conversely, IFN-αβ receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4(+) T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Viral / immunology
Antibody Specificity / immunology
B-Lymphocytes / drug effects
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
CD4 Antigens / genetics
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Cell Differentiation* / genetics
Gene Expression Profiling
Gene Expression Regulation
Germinal Center / immunology
Germinal Center / metabolism
Immunoglobulin Class Switching / genetics
Interferon Type I / genetics
Interferon Type I / metabolism*
Lymphocytic Choriomeningitis / genetics
Lymphocytic Choriomeningitis / immunology
Lymphocytic Choriomeningitis / metabolism
Lymphocytic choriomeningitis virus / immunology
Mice
Mice, Knockout
STAT1 Transcription Factor / metabolism
STAT3 Transcription Factor / deficiency
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Signal Transduction
T-Lymphocytes, Helper-Inducer / cytology*
T-Lymphocytes, Helper-Inducer / immunology
T-Lymphocytes, Helper-Inducer / metabolism*
Transcriptome

Substances

Antibodies, Viral
CD4 Antigens
Interferon Type I
STAT1 Transcription Factor
STAT3 Transcription Factor

Associated data

GEO/GSE55596

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding