Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus

Abstract

Systemic lupus erythematosus (SLE, lupus) is characterized by autoantibody-mediated organ injury. Follicular helper T cells (Tfh) orchestrate physiological germinal center (GC) B cell responses, while in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as SLE. We used blockade of IL-21 to dissect the mechanisms by which this cytokine promotes autoimmunity in murine lupus. Treatment of lupus-prone B6.Sle1.Yaa mice with an anti-IL-21 blocking antibody reduced titers of autoantibodies, delayed progression of glomerulonephritis and diminished renal infiltrating Tfh and T helper 1 (Th1) cells, and improved overall survival. Therapy inhibited excessive accumulation of Tfh cells co-expressing IL-21 and IFN-γ, and suppressed their production of the latter cytokine, albeit while not affecting their frequency. Anti-IL-21 treatment also led to a reduction in GC B cells, CD138hi plasmablasts, IFN-γ-dependent IgG2c production, and autoantibodies, indicating that Tfh-cell derived IL-21 is critical for pathological B cell cues in lupus. Normalization of GC responses were, in part, due to uncoupling of Tfh-B cell interactions, as evidenced by reduced expression of CD40L on Tfh cells and reduced B cell proliferation in treated mice. Our work provides mechanistic insight into the contribution of IL-21 to the pathogenesis of murine lupus, while revealing the importance of T-B cellular cross-talk in mediating autoimmunity, demonstrating that its interruption impacts both cell types leading to disease amelioration.

PD-1hiCXCR5– T peripheral helper cells promote B cell responses in lupus via MAF and IL-21

“…Cytometric, transcriptomic, and functional analyses presented here indicate that the PD-1 hi CXCR5 -Tph cell population shows a strong resemblance to Tfh cells, including expression of IL-21 and CXCL13 ex vivo, consistent with prior observations of Tph cells in rheumatoid synovium (22). Given the key roles of IL-21 in autoreactive B cell activation, autoantibody production, and renal injury in murine models of lupus, we hypothesize that IL-21 production is an important aspect of Tph cell function, although other pathologic roles independent of B cell-helper function are also possible (43,44). Subsequent studies will help to define the relationship between PD-1 hi and PD-1 + T cells and the relationship between Tph cells and Tfh cells in SLE patients.…”

The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice

“…Lpr model (58), anti-IL-21R mAb treatment in the NZB/W F1 model (59), and anti-IL-21 mAb treatment in the B6.Sle.Yaa model (60).…”

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…6 Inhibition of these signals by blocking antibodies results in loss of both GC Tfh and GC B cells. [41][42][43][44] After antigen clearance, GCs resolve and long- 49 and consequently, alterations in miRNA expression have been associated with several human diseases, such as cancer and autoimmunity. [49][50][51] Recent work also demonstrated that miRNAs serve as critical regulators of the immune system in a variety of cell types by directing lineage commitment, proliferation, differentiation, and migration.…”