IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Christoph Jandl; Sue M. Liu; Pablo F. Cañete; Joanna Warren; William E. Hughes; Alexis Vogelzang; Kylie Webster; Maria E. Craig; Gulbu Uzel; Alexander Dent; Polina Stepensky; Bärbel Keller; Klaus Warnatz; Jonathan Sprent; Cecile King

doi:10.1038/ncomms14647

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Christoph Jandl, Sue M. Liu, Pablo F. Cañete, Joanna Warren, William E. Hughes, Alexis Vogelzang, Kylie Webster, Maria E. Craig, Gulbu Uzel, Alexander Dent, Polina Stepensky, Bärbel Keller, Klaus Warnatz, Jonathan Sprent, Cecile King^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 + regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

Original language	English
Article number	14647
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14647
Publication status	Published - 17 Mar 2017

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Jandl, C., Liu, S. M., Cañete, P. F., Warren, J., Hughes, W. E., Vogelzang, A., Webster, K., Craig, M. E., Uzel, G., Dent, A., Stepensky, P., Keller, B., Warnatz, K., Sprent, J., & King, C. (2017). IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2. Nature Communications, 8, Article 14647. https://doi.org/10.1038/ncomms14647

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title = "IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2",

abstract = "T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 + regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.",

author = "Christoph Jandl and Liu, {Sue M.} and Ca{\~n}ete, {Pablo F.} and Joanna Warren and Hughes, {William E.} and Alexis Vogelzang and Kylie Webster and Craig, {Maria E.} and Gulbu Uzel and Alexander Dent and Polina Stepensky and B{\"a}rbel Keller and Klaus Warnatz and Jonathan Sprent and Cecile King",

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Jandl, C, Liu, SM, Cañete, PF, Warren, J, Hughes, WE, Vogelzang, A, Webster, K, Craig, ME, Uzel, G, Dent, A, Stepensky, P, Keller, B, Warnatz, K, Sprent, J & King, C 2017, 'IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2', Nature Communications, vol. 8, 14647. https://doi.org/10.1038/ncomms14647

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T1 - IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

AU - Jandl, Christoph

AU - Liu, Sue M.

AU - Cañete, Pablo F.

AU - Warren, Joanna

AU - Hughes, William E.

AU - Vogelzang, Alexis

AU - Webster, Kylie

AU - Craig, Maria E.

AU - Uzel, Gulbu

AU - Dent, Alexander

AU - Stepensky, Polina

AU - Keller, Bärbel

AU - Warnatz, Klaus

AU - Sprent, Jonathan

AU - King, Cecile

PY - 2017/3/17

Y1 - 2017/3/17

N2 - T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 + regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

AB - T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 + regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

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U2 - 10.1038/ncomms14647

DO - 10.1038/ncomms14647

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SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14647

ER -

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

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