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

Abstract

Aberrant expansion of follicular helper T (TFH) cells occurs in lupus patients. An unanswered question is whether an altered T cell receptor (TCR) repertoire is associated with this expansion. Here, we demonstrate that Blimp-1 repressed expression of the cathepsin S gene (Ctss) which encodes a cysteine protease that cleaves invariant chain and produces antigenic peptides for MHC class II loading. The increased CTSS in dendritic cells (DCs) of female Prdm1 conditional knockout (CKO) mice altered antigen presentation to CD4+ T cells. Analysis of Vβ CDR3s demonstrated a more diverse repertoire of TFH from female CKO mice. In vivo treatment of CKO mice with a CTSS inhibitor abrogated lupus-related phenotypes and reduced the diversity of the TFH TCR repertoire. Thus, Blimp-1 deficiency in DCs leads to a loss of appropriate regulation of Ctss expression in female mice thereby modulating antigen presentation and TFH repertoire to contribute to autoimmunity.