Research ArticleB CELLS

Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells

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Science Immunology  13 Sep 2019:
Vol. 4, Issue 39, eaaw7636
DOI: 10.1126/sciimmunol.aaw7636

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Unraveling a paradox

Germinal center T follicular helper (GC-TFH) cells are maintained through sustained TCR stimulation, but TCR activation induces IL-2 production and IL-2 receptor expression, which can inhibit TFH cells. Papillion et al. now explore this paradox using an influenza infection model, where they observe that GC-TFH cells can produce large amounts of IL-2 but are relatively unresponsive to this cytokine. Intrinsic IL-6 signaling is required to maintain this state of hyporesponsiveness, which involves a mechanism by which IL-6 prevents STAT5 from associating with Il2rb locus and thereby prevents up-regulation of IL-2Rβ (CD122). This allows GC-TFH cells to tolerate sustained TCR activation without triggering inhibitory IL-2 responses, thus revealing a regulatory mechanism that modulates GC-TFH cell generation (see the related Focus by Zhou and Yu).

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