title: Coordination between T helper cells, iNKT cells, and their follicular helper subsets in the humoral immune response against Clostridium difficile toxin B.
abstract: Activation of iNKT cells with the CD1d-binding glycolipid adjuvant α-galactosylceramide (α-GC) enhances humoral immunity specific for coadministered T-dependent Ag. However, the relationship between the iNKT cell and the classic T helper (Th) or T follicular helper (Tfh) function following this immunization modality remains unclear. We show that immunization with the C-terminal domain (CTD) of Clostridium difficile toxin B (TcdB), accompanied by activation of iNKT cells with α-GC, led to enhanced production of CTD-specific IgG, which was CD1d- and iNKT cell-dependent and associated with increased neutralization of active TcdB. Immunization with CTD plus α-GC followed by NP hapten-linked CTD increased NP-specific IgG1 titers in an NKT-dependent manner, suggesting that iNKT activation could enhance Th or Tfh function or that iNKT and iNKTfh cells could provide supplemental, yet independent, B cell help. Th, Tfh, iNKT, and iNKTfh cells were, therefore, examined quantitatively, phenotypically, and functionally following immunization with CTD or with CTD plus α-GC. Our results demonstrated that α-GC-activated iNKT cells had no direct effect on the numbers, phenotype, or function of Th or Tfh cells. However, CD4+T cell-specific ablation of the Bcl6 transcription factor demonstrated that Tfh and iNKTfh cells both contributed to B cell help. This work extends our understanding of the immune response to vaccination and demonstrates an important contribution by NKTfh cells to humoral immunity.
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Pragya
authors: P
authors: Rampuria
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Gillian A
authors: GA
authors: Lang
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: T Scott
authors: TS
authors: Devera
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Casey
authors: C
authors: Gilmore
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Jimmy D
authors: JD
authors: Ballard
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA mark-lang@ouhsc.edu.
authors: Mark L
authors: ML
authors: Lang
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry / Q000633:toxicity*; D001427:Bacterial Toxins / Q000737:chemistry / Q000633:toxicity*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D045142:Cross-Priming / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D006241:Haptens / Q000276:immunology; D056724:Immunity, Humoral / Q000187:drug effects; D007114:Immunization; D007074:Immunoglobulin G / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D055610:Antigens, CD1d; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005699:Galactosylceramides; D006241:Haptens; D007074:Immunoglobulin G; D007378:Interleukins; C493154:alpha-galactosylceramide; C031815:toxB protein, Clostridium difficile; D015847:Interleukin-4; D000098546:Interleukin-21
keywords: CD1d; T follicular helper; humoral immunity; iNKT follicular helper