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Increased cathepsin S in Prdm1-/- dendritic cells alters the TFH cell repertoire and contributes to lupus.

Authors
  • Kim, Sun Jung1
  • Schätzle, Sebastian2
  • Ahmed, S Sohail3
  • Haap, Wolfgang3
  • Jang, Su Hwa1
  • Gregersen, Peter K4
  • Georgiou, George2
  • Diamond, Betty1
  • 1 Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
  • 2 Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
  • 3 Immunology, Inflammation, and Infectious Diseases (Disease and Therapeutic Area), Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland. , (Switzerland)
  • 4 Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
Type
Published Article
Journal
Nature Immunology
Publisher
Springer Nature
Publication Date
Sep 01, 2017
Volume
18
Issue
9
Pages
1016–1024
Identifiers
DOI: 10.1038/ni.3793
PMID: 28692065
Source
Medline
License
Unknown

Abstract

Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules. The increased CTSS expression in dendritic cells (DCs) from female mice with dendritic cell-specific conditional knockout of Prdm1 (CKO mice) altered the presentation of antigen to CD4+ T cells. Analysis of complementarity-determining region 3 (CDR3) regions containing the β-chain variable region (Vβ) demonstrated a more diverse repertoire of TFH cells from female CKO mice than of those from wild-type mice. In vivo treatment of CKO mice with a CTSS inhibitor abolished the lupus-related phenotype and reduced the diversity of the TFH cell TCR repertoire. Thus, Blimp-1 deficiency in DCs led to loss of appropriate regulation of Ctss expression in female mice and thereby modulated antigen presentation and the TFH cell repertoire to contribute to autoimmunity.

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