BBhlhe40 promotes TH2 cell-mediated anti-helminth immunity and reveals cooperative Csf2rb family cytokines

Authors: JARJOUR, NICHOLAS - Washington University School Of Medicine; BRADSTREET, TARA - Washington University School Of Medicine; SCHWARZKOPF, ELIZABETH - Washington University School Of Medicine; COOK, MELISSA - Washington University School Of Medicine; LAI, CHIN-WEN - Washington University School Of Medicine; HUANG, STANLEY - Washington University School Of Medicine; TANEJA, RESHMA - National University Of Singapore; STAPPENBECK, THADDEUS - Washington University School Of Medicine; Urban, Joseph; EDELSON, BRIAN - Washington University School Of Medicine

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/1/2020
Publication Date: 2/15/2020
Citation: Jarjour, N.N., Bradstreet, T.R., Schwarzkopf, E.A., Cook, M.E., Lai, C., Huang, S., Taneja, R., Stappenbeck, T.S., Urban Jr, J.F., Edelson, B.T. 2020. BBhlhe40 promotes TH2 cell-mediated anti-helminth immunity and reveals cooperative Csf2rb family cytokines. Journal of Immunology. 204(4):923-932. https://doi.org/10.4049/jimmunol.1900978.
DOI: https://doi.org/10.4049/jimmunol.1900978

Interpretive Summary: Helminthic parasites (worms) manipulate the immune system to establish chronic infections. Worm infections are characterized by the induction of host signaling molecules called alarmins that stimulate an allergic type immune response that can often eliminate the worm from humans and livestock. This is most evident in experimental worm infections conducted in the laboratory. Worm infections are most economically important when they compromise the health and well being of livestock to reduce productivity. The current study showed that components of immunity to worms is dependent on cellular factors that control the expression of protein messenger molecules that can eliminate the infection through altered intestinal physiology in rodents. These observations point to a need to demonstrate the role of similar factors in livestock since they can be used as a target to better control parasitic infections that increase the cost of animal production and the quality of food available to the US public. This information is important to those interested in immune regulation of the responses to parasitic infection in livestock and humans.

Technical Abstract: The cytokines GM-CSF and IL-5 are thought to possess largely divergent functions despite a shared dependence on the common beta (ßC) 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 ispensable 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 rec-hallenge 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. ßC chain-deficient, but not GM-CSF-deficient, mice re-challenged 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 ßC chain-dependent cytokines.