title: PU.1 Expression in T Follicular Helper Cells Limits CD40L-Dependent Germinal Center B Cell Development.
abstract: PU.1 is an ETS family transcription factor that is important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development and in limiting Th2 cytokine production. Whether PU.1 has functions in other Th lineages is not clear. In this study, we examined the effects of ectopic expression of PU.1 in CD4(+) T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1(lck-/-)) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1(lck-/-) mice had increased numbers of Tfh cells, increased germinal center B cells (GCB cells), and increased Ab production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1(lck-/-) mice compared with control mice. Finally, although blockade of IL-21 did not affect GCB cells in Sfpi1(lck-/-) mice, anti-CD40L treatment of immunized Sfpi1(lck-/-) mice decreased GCB cell numbers and Ag-specific Ig concentrations. Together, these data indicate an inhibitory role for PU.1 in the function of Tfh cells, germinal centers, and Tfh-dependent humoral immunity.
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Olufolakemi
authors.initials: O
authors.lastname: Awe
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hufford
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Duy
authors.initials: D
authors.lastname: Pham
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202.
authors.forename: Hua-Chen
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Jabeen
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and mkaplan2@iupui.edu.
authors.forename: Mark H
authors.identifier: http://orcid.org/0000-0002-2923-8245
authors.initials: MH
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D056724:Immunity, Humoral / Q000502:physiology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000098546:Interleukin-21; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D023201:CD40 Ligand; D007378:Interleukins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000098546:Interleukin-21; D000099232:Proto-Oncogene Protein Spi-1