1. IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2.
- Author
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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, and King C
- Subjects
- Adolescent, Animals, Child, Female, Humans, Immunity, Humoral immunology, Immunologic Deficiency Syndromes genetics, Infant, Interleukin-21 Receptor alpha Subunit immunology, Interleukins immunology, Male, Mice, Mice, Knockout, Receptors, CXCR4 immunology, Interleukin-21, Cell Proliferation genetics, Immunity, Humoral genetics, Interleukin-2 immunology, Interleukin-21 Receptor alpha Subunit genetics, Interleukins genetics, Proto-Oncogene Proteins c-bcl-6 immunology, T-Lymphocytes, Regulatory immunology
- 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.- Published
- 2017
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