RGD Reference Report - IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.

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IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.
Authors:	Eto, Danelle Lao, Christopher DiToro, Daniel Barnett, Burton Escobar, Tania C Kageyama, Robin Yusuf, Isharat Crotty, Shane
Citation:	Eto D, etal., PLoS One. 2011 Mar 14;6(3):e17739. doi: 10.1371/journal.pone.0017739.
RGD ID:	127285543
Pubmed:	PMID:21423809 (View Abstract at PubMed)
PMCID:	PMC3056724 (View Article at PubMed Central)
DOI:	DOI:10.1371/journal.pone.0017739 (Journal Full-text)
Cytokines are important modulators of lymphocytes, and both interleukin-21 (IL-21) and IL-6 have proposed roles in T follicular helper (Tfh) differentiation, and directly act on B cells. Here we investigated the absence of IL-6 alone, IL-21 alone, or the combined lack of IL-6 and IL-21 on Tfh differentiation and the development of B cell immunity in vivo. C57BL/6 or IL-21(-/-) mice were treated with a neutralizing monoclonal antibody against IL-6 throughout the course of an acute viral infection (lymphocytic choriomeningitis virus, LCMV). The combined absence of IL-6 and IL-21 resulted in reduced Tfh differentiation and reduced Bcl6 protein expression. In addition, we observed that these cytokines had a large impact on antigen-specific B cell responses. IL-6 and IL-21 collaborate in the acute T-dependent antiviral antibody response (90% loss of circulating antiviral IgG in the absence of both cytokines). In contrast, we observed reduced germinal center formation only in the absence of IL-21. Absence of IL-6 had no impact on germinal centers, and combined absence of both IL-21 and IL-6 revealed no synergistic effect on germinal center B cell development. Studying CD4 T cells in vitro, we found that high IL-21 production was not associated with high Bcl6 or CXCR5 expression. TCR stimulation of purified naïve CD4 T cells in the presence of IL-6 also did not result in Tfh differentiation, as determined by Bcl6 or CXCR5 protein expression. Cumulatively, our data indicates that optimal Tfh formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh differentiation.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
IL21	Human	Arenaviridae infectious disease		ISO	Il21 (Mus musculus)		RGD
Il21	Rat	Arenaviridae infectious disease		ISO	Il21 (Mus musculus)		RGD
Il21	Mouse	Arenaviridae infectious disease		IMP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Il21 (interleukin 21)

Genes (Mus musculus)

Il21 (interleukin 21)

Genes (Homo sapiens)

IL21 (interleukin 21)

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IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.