Nonredundant Roles of IL-21 and IL-4 in the Phased Initiation of Germinal Center B Cells and Subsequent Self-Renewal Transitions

Abstract

We examined the unique contributions of the cytokines IL-21 and IL-4 on germinal center (GC) B cell initiation and subsequent maturation in a murine model system. Similar to other reports, we found T follicular helper cell (Tfh) expression of IL-21 begins prior to Tfh migration into the B cell follicle and precedes that of IL-4. Consistent with this timing, IL-21 signaling has a greater influence on the peri-follicular pre-GC B cell transition to the intra-follicular stage. Notably, Bcl6hi B cells can form in the combined absence of IL21R and STAT6 derived signals, however these nascent GC B cells cease to proliferate and are more prone to apoptosis. When B cells lack either IL21R or STAT6, aberrant GCs form atypical centroblast and centrocytes that differ in their phenotypic maturation and co-stimulatory molecule expression. Thus IL-4 and IL-21 play non-redundant roles in the phased progression of GC B cell development that can initiate in the combined absence of these cytokine signals.

BAFF, IL‐4 and IL‐21 separably program germinal center‐like phenotype acquisition, BCL6 expression, proliferation and survival of CD40L‐activated B cells in vitro

“…Similarly, IL‐21 transcription in T cells is observed within 3 days of immunization in response to alum‐precipitated protein immunization, suggesting the two cytokines both have the potential to contribute to early lymphoid B cell responses. A role for IL‐21 is indeed apparent, as IL‐21R −/− B cell GC and plasmablast abundances are 10–20‐fold diminished relative to wild type responses as early as 4 days after immunization . In contrast, perhaps surprisingly, with the exception of a clear impact on IgE production, IL‐4 signals tend to have little or no inhibitory effect on the earliest GC and extrafollicular plasmablast response.…”

Germinal center B cell initiation, GC maturation, and the coevolution of its stromal cell niches

“…both IL-21R and IL-4R signal via the Janus kinase molecules JAK1 and JAK3 [202][203][204][205]. However, these cytokine receptors activate different signal transducer and activator of transcription (STAT) molecules.Whereas IL-21 predominantly activates STAT3 and STAT1, and to a lesser extent STAT5,[206][207][208][209] , IL-4, and IL-13 uniquely and requisitely activate STAT6210,211 .The results of a recent study we performed suggest that B cell signaling by these cytokines may influence GC B cells at different stages 182. These experiments employed the cell transfer of antigenspecific B cells that were either deficient in IL-21R, STAT6, or both in order to assess the impact of IL-21 and IL-4/IL-13 to B cells intrinsically.…”

“…179,180 However, once GC B cells have migrated into the follicle interior, they again have access to a rich source of antigen within the FDC network. 182,[191][192][193][194] In vitro, both IL-21 and IL-4 can enhance the transcription and/or translation of Bcl6 in B cells. 195,196 Both cytokines are also known to promote ASC formation.…”

“…22,[197][198][199][200][201] In the case of IL-21, an inability to signal via its receptor has a direct effect on B cells, resulting in lower Bcl6 levels among the more limited number of GC B cells that form. 182,191,192 IL-4R and IL-21R complexes activate distinct signaling pathways.…”

“…zonal segregation requires, by definition, the presence of GC B cells outside of the FDC network, but as described below there are several other unique features of the DZ compartment that evolve during the course of the response. The emerging centroblasts typically form both a collection immediately under the FDC network as well as a loose column that stretches toward the T-zone border (Figure 3B) 141,182. in some but not all GCs, there are DZ areas that are not filled by a CRC network 242.…”