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Abstract
SummaryT helper 2 (Th2) cells regulate helminth infections, allergic disorders, tumor immunity, and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2 signaling molecules. Although steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterized. Here, we demonstrate production of the steroid pregnenolone by Th2 cells in vitro and in vivo in a helminth infection model. Single-cell RNA sequencing and quantitative PCR analysis suggest that pregnenolone synthesis in Th2 cells is related to immunosuppression. In support of this, we show that pregnenolone inhibits Th cell proliferation and B cell immunoglobulin class switching. We also show that steroidogenic Th2 cells inhibit Th cell proliferation in a Cyp11a1 enzyme-dependent manner. We propose pregnenolone as a “lymphosteroid,” a steroid produced by lymphocytes. We speculate that this de novo steroid production may be an intrinsic phenomenon of Th2-mediated immune responses to actively restore immune homeostasis.
Highlights
An effective immune response is required for successful pathogen clearance
Single-cell RNA sequencing and quantitative PCR analysis suggest that pregnenolone synthesis in T helper 2 (Th2) cells is related to immunosuppression
We show that pregnenolone inhibits T helper (Th) cell proliferation and B cell immunoglobulin class switching
Summary
An effective immune response is required for successful pathogen clearance. Depending upon the immunogen or allergen source (e.g., infection, commensal microorganism, or self-antigen), naive Th cells differentiate into several subtypes, including Th1, Th2, Th17, and iTreg, based on their cytokine profile and function (Zhu et al, 2010). Upon extracellular pathogen infection (e.g., helminth infection), innate immune cells guide naive Th cells toward a Th2 phenotype. During type 2 immune responses, antigen experienced Th cells proliferate and differentiate toward the Th2 subtype and function through production of various effector cytokines, including interleukin-4 (IL-4), IL-5, IL-9, and IL-13, and at least two suppressor cytokines IL-10 and transforming growth factor (TGF)-b1 (Murphy et al, 2008). The active restoration or termination of a type 2 immune response is not well understood, though the importance of active termination has been discussed (Marrack et al, 2010; Viganoet al., 2012)
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