Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas 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 systemic lupus erythematosus. 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 Ab reduced titers of autoantibodies, delayed progression of glomerulonephritis and diminished renal-infiltrating Tfh and Th1 cells, and improved overall survival. Therapy inhibited excessive accumulation of Tfh cells coexpressing 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 was, in part, caused by 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.
This work was supported by grants from AbbVie (to J.C.) and the Alliance for Lupus Research (to J.C.), as well as by National Institutes of Health Grants R37AR040072, R01AR068994, and P30AR053495 (to J.C.). A.S. was supported by a Scientist Development Award from the American College of Rheumatology Research Foundation, as well as by National Institutes of Health Grant T32 AR07107 and a grant from the Robert E. Leet and Clara Guthrie Patterson Trust.
Abbreviations used in this article:
- B cell lymphoma 6 protein
- Dulbecco's PBS
- germinal center
- geometric mean fluorescence intensity
- Meso Scale Discovery
- systemic lupus erythematosus
- follicular Th.
- Received September 29, 2016.
- Accepted January 26, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.