Karine SERRE, PhD
IMMUNOLOGIST
Latest Posts
21/01/2016
Psoriasis is an autoimmune disease and NOT a chronic inflammatory disease!12/05/2015
CALL For PAPERS: “Innate T Cell Development and Functions in Immune Diseases”28/08/2014
XL Annual Meeting of the Sociedade Portuguesa de Imunologia 13-15th October 201413/04/2013
Beginnings of breaking down the differentiation program of innate IL-17-production27/01/2013
The improbable trio NKG2D – γδ T cells – IgE!!IL-25
Is there a role for the IL-25/IL-17RB signalling pathway in inducing IL-4 production by CD4 T cells in response to alum-precipitated proteins in vivo?
Alum-precipitated protein antigen is a good model to study Th2 immune responses in vivo. It triggers the production of Th2-cytokines (IL-4, IL-13), Th2-associated transcription factors (GATA-3, c-Maf, NIP45), and switching to IgG1 and IgE (1-5). In addition, alum-precipitated proteins induce strong germinal centre reactions and with these induce follicular helper T (TFh) cells, a subset different from the Th2 cells, which have been found to produce IL-4.
Although insight into alum’s mode of action is incomplete it has proven adjuvant efficacy in many vaccine formulations (6-8). Surprisingly, its adjuvanticity and the induction of most of the Th2-features are Toll-like receptor (TLR)- and TLR signaling-independent (9-12). Alum-precipitated proteins can activate caspase-1 and induce proinflammatory cytokines such as IL-1b, IL-18 (13) and IL-33 (14). It has also been shown that some of alum’s effects are mediated through the inflammasome NLRP3 (nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3) (12, 14), possibly in part via the induction of uric acid (15). Nevertheless, these mechanisms do not fully explain the way alum promotes strong Th2-directed antibody responses. Several groups including our own have shown that IL-4 production induced by alum-precipitated protein in vivo is predominantly brought about without IL-4-signalling (1, 4, 5, 16). In this context, we propose a role for the IL-25/IL-17RB signalling pathway in inducing Th2 cells.
IL-17RB is selectively expressed by CD4 T cells responding to alum-precipitated protein in vivo
I have shown that the expression of IL-17RB is strongly associated with CD4 Th2 immune response to alum-precipitated protein (3) (Fig. 1). 
Thus the IL-25/IL-17RB pathway may be part of the mechanism by which alum provokes a Th2-type of immune response. Arguments in favour are the following: the receptor IL-17RB binds to IL-17B and IL-17E (IL-25). IL-25 has been found to play major roles during Th2 responses and, for instance, IL-25 injection or systemic over-expression in transgenic mice provokes the up-regulation of Th2-features or proallergic pathologies (17-20). In addition, a role for IL-25 has been identified in Th2-immune responses such as those against helminth parasites (19, 21), and airway asthma inflammation (22, 23). Finally, human and mouse CD4 Th2 cells produce IL-25 (20, 24-26).
CD8 T cells proliferate in response to alum-precipitated protein in vivo but do not express Th2-cytokines or IL-17RB
IL-4-producing CD8 T cells can be induced in vitro by TCR ligation in the presence of IL-4 (27-30). 
Thus we questioned whether IL-4-producing CD8 T cells would be induced in vivo in response to primary immunization with alum-precipitated protein. The approach has been to compare the polarization of transgenic naïve ovalbumin-specific CD4 (OTII) and CD8 (OTI) T cells during their response to alum-precipitated ovalbumin (alumOVA). By addressing this question we have obtained further insight into the way early Th2-features are acquired by CD4 T cells in vivo in response to alum-precipitated protein.
Although both CD4 and CD8 OVA-specific T cells proliferate (30) in response to alumOVA, the acquisition of Th2-features, such as IL-4 and IL-13 mRNA up-regulation, is exclusively confined to CD4 T cells (Fig. 2). In addition, we confirm that mRNA specific for IL-17RB is strongly induced in vivo in alumOVA-responding OTII cells, but not in OTI cells responding to the same antigen (Fig. 2).
Conclusions
These findings indicate that the induction of IL-17RB expression is a selective feature of CD4 T cells making a Th2 response in response to alum-precipitated antigen in vivo. This indication of selectivity is also confirmed by the IL-17RB mRNA expression that is induced in OTII cells responding to alumOVA but not in the OTI cells responding within the same microenvironment in the same LN to the same antigen. This is of interest, for OTI cells although proliferating and producing IFN-g, do not acquire any Th2-features in response to alumOVA (30).
As previously reported (26), it likely that IL-17RB engagement is involved in the maturation rather than primary induction of Th2 response to alumOVA as this receptor is itself induced in OTII cells during the response.
Current evidence suggests that IL-25 can induce type-2 cytokine secretion directly from Th2 cells, but significantly can also induce IL-4 and IL-13 secretion from an innate cell (non-T non-B) population (19). Thus, IL-25 may be required for the generation of an innate type cell which may contribute to the initial source of Th2 cytokines at the initiation of an adaptive type-2-mediated response, suggesting that IL-25 can act both at the induction of type-2 immunity and in the maintenance of an existing response.
We have been unable to detect IL-25 mRNA in naïve or immunized LN cell suspensions in the present study (data not shown). Nevertheless, innate immune cells (20, 26, 31) have been reported to produce this cytokine. It will be of interest to see if the production of IL-25, for instance in dendritic cells, relies on a signaling pathway dependent on the inflammasome (12, 14, 15). Further studies are on going to determinate the exact role of IL-25 during the response to alum-precipitated protein antigen.
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