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.