Deficiency in Bhlhe40 impairs resistance to H. polygyrus bakeri and reveals novel Csf2rb-dependent regulation of anti-helminth immunity

Abstract

The cytokines GM-CSF and IL-5 are thought to possess largely divergent functions despite a shared dependence on the common beta ({beta}C) chain to initiate signaling. Although IL-5 is part of the core type 2 cytokine signature and is required for protection against some helminths, it is dispensable for immunity to others, such as Heligmosomoides polygyrus bakeri (H. polygyrus). Whether this is due to compensatory mechanisms is unclear. The transcription factor Bhlhe40 has been shown to control GM-CSF production and is proposed to be a novel regulator of T helper type 2 cells. We have found that Bhlhe40 is required in T cells for a protective memory response to secondary H. polygyrus infection. H. polygyrus rechallenge elicited dramatic Bhlhe40-dependent changes in gene and cytokine expression by lamina propria CD4+ T cells and in vitro-polarized TH2 cells, including induction of GM-CSF and maximal production of type 2 cytokines including IL-5. {beta}C chain-deficient, but not GM-CSF-deficient, mice rechallenged with H. polygyrus had severely impaired protective immunity. Our results demonstrate that Bhlhe40 is an essential regulator of TH2 cell immunity during helminth infection and reveal unexpected redundancy of {beta}C chain-dependent cytokines.