Figure 1: a) Mouse model of adoptive cell transfer used to genetically manipulate the IL-21 production and sensing transferring ovalbumin (OVA)-specific IL-21 sufficient (Il21Gfp/+ ) or IL-21 deficient (Il21Gfp/Gfp ) T cells together with IL-21R sufficient (Il21r+/+ ) or deficient (Il21r-/- ) hen egg lysozyme (HEL) specific B cells followed by immunization with the cross linked peptide HEL2 x OVApep. b) Early on in the immune response, the availability of IL-21 in the microenvironment plays a critical role in regulating T cell expansion and Tfh differentiation, impacting the density of Tfh cells and ultimately determining the magnitude of the GC response.
After the establishment of the GC, increasing IL-21 availability promoted the centroblast phenotype in GC B cells, confirming a previous report 6.
To determine if the IL-21 activity in GC B cells was restricted to cognate T cell secreting IL-21 during the T-B synapse, mice deficient in both IL-21R and IL-21 adoptively received OVA-specific T cells able to produce and sense IL-21 (Il21r+/+Il21Gfp/+ ), together withIl21r+/+ B1-8 B cells, which are specific for the hapten NP. The recipient mice were then dually immunized with OVA and NP-KLH (Fig. 2). In this system NP specific B cells could not receive IL-21 from endogenous cognate T cells that recognized KLH, but IL-21 secreted by the non-cognate OVA specific T cells, in a dose dependent manner, supported the NP specific B cell proliferation, centroblast identity and plasma cell differentiation after immunization. This demonstrated for the first time that IL-21 acts locally in a non-cognate fashion to sustain GC B cell proliferation and differentiation.