IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation

Abstract

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.

T-cell help in the germinal center: homing in on the role of IL-21

“…It was initially suggested that IL-21 was required for Tfh cell differentiation ( 50 , 51 ), however, subsequent work established that Tfh cells could still form in animals with defective IL-21 signaling ( 25 , 26 , 52 ). Nevertheless, IL-21 has been shown to support Tfh cell expansion and maintenance ( 25 , 53 , 54 ) and it has a marked impact on the ratio of Tfh to follicular regulatory T cells (Tfr) in transient as well as autoimmune GC ( 55 , 56 ).…”

“…While GC are typically dominated by dark zone cells in both mice and humans ( 62 , 63 ) several studies have now noted marked skewing towards a light zone phenotype in GC B cells from IL-21- and IL-21R-deficient mice ( Fig. 2 ) ( 46 , 54 , 55 , 57 , 58 , 64 ). Defects in IL-21 signaling have been found to result in impaired dark zone compartments in immunization-induced GC ( 54 , 57 , 58 ) as well as in GC triggered by autoimmunity ( 54 ) and viral infection ( 64 ).…”

“…2 ) ( 46 , 54 , 55 , 57 , 58 , 64 ). Defects in IL-21 signaling have been found to result in impaired dark zone compartments in immunization-induced GC ( 54 , 57 , 58 ) as well as in GC triggered by autoimmunity ( 54 ) and viral infection ( 64 ). Furthermore, IL-21 has been shown to modulate GC dark zone formation in both mice with wild-type polyclonal ( 54 , 58 ) and restricted transgenic T cell and B-cell receptor repertoires ( 46 , 57 ).…”

“…Defects in IL-21 signaling have been found to result in impaired dark zone compartments in immunization-induced GC ( 54 , 57 , 58 ) as well as in GC triggered by autoimmunity ( 54 ) and viral infection ( 64 ). Furthermore, IL-21 has been shown to modulate GC dark zone formation in both mice with wild-type polyclonal ( 54 , 58 ) and restricted transgenic T cell and B-cell receptor repertoires ( 46 , 57 ). The identification of a role for IL-21 in GC B-cell proliferation, and GC dark zone formation helps reconcile the defective GC expansion, maintenance, and reduced affinity maturation that have long been observed in animals with impaired IL-21 signaling ( Table 1 ).…”

“…Models depicting effects of changes in IL-21 signaling on GC dark zone/light zone ratios and GC output. GC with reduced or no IL-21 signaling (left) have reduced dark zone compartments and yield fewer plasma cells than GC with normal IL-21 levels (middle) ( 25 , 26 , 38 , 54 , 58 , 64 ). Elevated IL-21 levels (right) lower the B-cell positive selection threshold and allow more B-cell clones to enter the GC dark zone ( 54 , 60 , 61 ).…”