Cutting Edge: IL-21 Derived from Human Follicular Helper T Cells Acts as a Survival Factor for Secondary Lymphoid Organ, but Not for Bone Marrow, Plasma Cells

Abstract

IL-21 induces the differentiation of activated B lymphocytes into plasma cells (PC), but its direct effect on PC remains uncertain. This study analyzes the role of IL-21 on human in vivo-generated PC. IL-21R was clearly expressed on PC from the human tonsil, the lymph node, and the spleen (secondary lymphoid organs [SLO]) but barely on terminally mature bone marrow PC. IL-21 enhanced Ig secretion by isolated SLO PC but not bone marrow PC. Tonsillar T follicular helper (Tfh) lymphocytes are known to secrete IL-21. Purified Tfh cells induced a marked increase of Ig production by tonsillar PC, and this effect was impaired when endogenous IL-21 production was blocked. IL-21 provoked a rapid and transient phosphorylation of STAT3 in tonsillar PC. Tfh cells or exogenous IL-21 reduce tonsillar PC apoptosis and increases PC recovery but does not modify their nonproliferating status. These results suggest that IL-21 derived from Tfh cells acts as a survival factor for SLO PC in vivo.

STAT-3 Activation by Differential Cytokines Is Critical for Human In Vivo–Generated Plasma Cell Survival and Ig Secretion

“…Subsequently, CD31 + cells were purified from the To non-T cell fraction by immunomagnetic cell selection to pre-enrich PC (17,32 …”

“…The different auxiliary cell types, and the cytokines and other molecules reported as participants in PC survival niches have been recently revised (24,31). In a previous study, we have demonstrated that human SLO, but not BM, PCs express IL-21R and respond to IL-21 by activating STAT-3 and increasing their survival (32). IL-10 induces the differentiation of B lymphocytes to PCs (33); nevertheless, its role in PCs has not been clarified.…”

A critical role of T follicular helper cells in human mucosal anti-influenza response that can be enhanced by immunological adjuvant CpG-DNA

“…IL-21 has been suggested to play an important role in T FH differentiation (Rodríguez-Bayona et al, 2012). We showed that stimulation with CpG-DNA enhanced IL-21 production that was (predominantly IgG), but were unable to help naïve B cells (Bentebibel et al, 2013).…”

IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

“…Additionally, this effect was impaired when T FH cell-derived IL-21 was blocked. 26 Additionally, IgE and other immunoglobulin isotypes were observed to be switched under the influence of T cell-derived cytokines. 24 For instance, IL-10 was identified as the switch factor for IgG4, 27 and IL-21 was shown to be the switch factor for human IgG1 and IgG3.…”

“…76 However, the changes in Bcl-6 expression in autoimmune disease remain disputed. Studies have reported elevated Bcl-6 mRNA levels in the CD4 1 T cells of RA patients 26 and SLEprone mice. 69 The breakdown of the Blimp-1 and Bcl-6 balance leads to auto-PC accumulation, which tends to cause autoimmune disease.…”