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.

What We Do and Do Not Know about Women and Kidney Diseases; Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Women’s Day

“…Estrogen’s primary effects are mediated by transcription activity of the intracellular estrogen receptors, whose profile is altered in T cells from female SLE patients [69, 70]. The cathepsin S protein has recently been identified as a potential cause of lupus, triggering the immune system to attack healthy cells, particularly in females [71]. Numerous non-HLA genetic markers may predispose individuals of European, Hispanic, and Afro-American ancestry to lupus [72].…”

What we do and do not know about women and kidney diseases – questions unanswered and answers unquestioned: Reflection on World Kidney Day and International Woman’s Day

“…Oestrogen’s primary effects are mediated by transcription activity of the intracellular oestrogen receptors, whose profile is altered in T‐cells from female SLE patients . Cathepsin S protein has recently been identified as a potential cause of lupus, triggering the immune system to attack healthy cells, particularly in females . Numerous non‐HLA genetic markers may predispose individuals of European, Hispanic, and Afro‐American ancestry to lupus .…”

What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: Reflection on World Kidney Day and International Woman’s Day

“…Основное действие эстрогенов медиируется транскрипционной актив-ностью рецепторов к эстрогену, при том что у жен-щин с СКВ Т-клеточный рецепторный профиль этих рецепторов нарушен [69,70]. Недавно была идентифицирована еще одна возможная причина СКВ -белок катепсин S, являющийся триггером иммунной атаки на здоровые клетки, особенно у женщин [71]. Многочисленные генетические мар-керы, не относящиеся к HLA-системе, могут быть основой предрасположенности к СКВ у лиц евро-пейского, латиноамериканского и афроамерикан-ского происхождения [72].…”