A GDF-15–GFRAL axis controls autoimmune T cell responses during neuroinflammation

nature immunology Article https://doi.org/10.1038/s41590-025-02406-1 A GDF-15–GFRAL axis controls autoimmune T cell responses during neuroinflammation Received: 9 March 2025 Accepted: 5 December 2025 Published online: xx xx xxxx Check for updates Jana K. Sonner 1,2, Audrey Kahn1,2, Lars Binkle-Ladisch 1,2, Jan Broder Engler 1,2, Beatrice Haack3, Christina Zeiler1,2, Lisa Unger1,2, Simone Bauer1,2, Felix Fischbach1,2, Giovanni Almanzar4, Mark Walkenhorst1,2, Christina Mayer1,2, Aneta Kolakowska1,2, Sebastian Graute 5, Caren Ramien 1,2, Ingo Winschel 1,2, Nicola Rothammer1,2, Markus Heine5, Verena Horneffer-van der Sluis6, Vincent Thiemann3, Vanessa Vieira1,2, Nina Meurs 1,2, Thomas Renné6,7,8, Martina Prelog4, Sebastian Beck Jørgensen9, Randy J. Seeley 10, Anke Diemert11, Petra C. Arck 2,11, Stefan M. Gold1,12, Joerg Heeren 5, Jörg Wischhusen3 & Manuel A. Friese 1,2 Inflammatory activity during multiple sclerosis (MS) often improves during pregnancy, suggesting that pregnancy-related immune adaptations affect the disease. Here we show that growth/differentiation factor-15 (GDF-15) increases during pregnancy and correlates with a reduced rate of MS relapses. GDF-15 also accumulates in the inflamed central nervous system, and its absence impairs inflammation resolution in a mouse model of MS. GDF-15 suppresses autoimmune T cell responses through an indirect signaling pathway involving the activation of GDNF family receptor α-like (GFRAL) on brainstem neurons. Therapeutic approaches, including neuronal gene delivery, recombinant GDF15 administration and targeted chemogenetic activation of GFRAL-positive neurons induce β-adrenergic signaling and norepinephrine synthesis in the spleen, leading to decreased expression of integrins on T cells required for transmigration across the blood–brain barrier and confer protection against neuroinflammation in preclinical models of MS. These findings position GDF-15 as a crucial neuroimmune mediator and the GDF-15–GFRAL axis as promising target for MS. MS is a common neuroinflammatory disorder that primarily affects individuals in early adulthood. It likely arises from a dysregulated immune response directed against central nervous system (CNS) self-antigens, leading to inflammatory CNS lesions. Autoreactive T cells cross the blood–brain barrier, activate CNS-resident myeloid cells and drive progressive demyelination and neurodegeneration1,2. To counteract tissue inflammation, the body relies on inherent mechanisms of immune tolerance. During pregnancy, a substantial reduction in inflammatory disease activity is observed in MS3,4 and other T cell-mediated autoimmune diseases, such as rheumatoid arthritis or Graves’ disease5, emphasizing the potent immunomodulatory impact of pregnancy—effects A full list of affiliations appears at the end of the paper. Nature Immunology partly reproduced in animal models6–8. Treatment with the pregnancy hormone estriol is effective in autoimmune encephalomyelitis9 and shows some effects in clinical trials of nonpregnant women with MS, but does not fully recapitulate the pregnancy-related reduction in relapse rates10. This suggests that a more complex regulatory network governs transient tolerance during pregnancy. Elucidating the key mechanisms behind this evolutionarily selected immune tolerance, which allows the maternal body to accept the semi-allogeneic fetus, could be crucial for developing new therapeutic strategies for immune-mediated inflammatory diseases. Bidirectional communication between the nervous and the immune system—immunoception—is receiving increasing attention, e-mail: Article with evidence showing how immune imbalances activate specific brain regions and how neuronal regulation shapes inflammatory diseases11–16. One molecule that may link reduced inflammatory activity in pregnant individuals who have MS with neuronal control of peripheral immunity is GDF-15. During pregnancy, trophoblasts and immature dendritic cells in the placenta produce GDF-15, with maternal plasma concentrations rising as the fetus develops17. Most circulating GDF-15 originates from the fetus rather than maternal reproductive cells18. Low GDF-15 serum levels have been linked to miscarriage19, suggesting a key role in fetal immune tolerance and potentially in suppressing autoreactive CNS-directed T cell responses. Consistently, GDF-15 suppresses lymphoproliferation in systemic lupus erythematosus20. Previous work identified GDNF family receptor α-like (GFRAL) as the canonical GDF-15 receptor responsible for inducing cachexia and anorexia21,22. GFRAL is primarily expressed in brainstem neurons23, and no alternative immune cell receptor has been found, despite studies reporting direct T cell modulation by GDF-1524, inhibition of neutrophil and macrophage chemotaxis25,26, and reduced cytotoxicity of tumor-infiltrating macrophages27, as well as GFRAL-independent modulation of myeloid cells28. GFRAL-expressing neurons cluster in the area postrema and to a lesser extent the nucleus tractus solitarius (NTS). Because these regions possess highly fenestrated capillaries, they are ideally positioned to sense soluble circulating mediators29, including GDF-15 released by the fetus or from stressed tissues18,30. In this study, we explore how GDF-15 regulates autoimmune T cell responses downstream of GFRAL and demonstrate the effect of immunoception on neuroinflammation. Results GDF-15 expression is increased in human and mouse pregnancies To assess whether GDF-15 contributes to fetomaternal immune tolerance, we measured its levels in human and mouse pregnancies. As reported31, plasma GDF-15 gradually increased in human pregnancy compared to age-matched and body mass index-matched nonpregnant controls (Fig. 1a and Supplementary Table 1). In syngeneic C57BL/6J matings, we detected only a minor increase in systemic GDF-15 during the third trimester. In contrast, in semi-allogeneic matings, which mimic exposure to foreign antigens derived from the fetus, GDF-15 levels surged nearly fourfold (Extended Data Fig. 1a,b). Although a study postulated that a lack of GDF-15 during human pregnancy has no impact on fetal development or pregnancy32, we found that lower plasma GDF-15 in pregnant mice correlated with reduced litter size (Extended Data Fig. 1c). We further observed a striking difference between women experiencing a miscarriage and those undergoing an elective abortion (Fig. 1b and Supplementary Table 2). Notably, when stratifying pregnant individuals with MS according to their relapse activity during pregnancy, which can occasionally occur despite substantial pregnancy-related immunosuppression3,4, we found that relapse activity was associated with reduced serum GDF-15 in early to mid-pregnancy (Fig. 1c and Supplementary Table 3). This finding suggests that pregnancy-induced GDF-15 may play a key role in mediating immunosuppression in the context of neuroinflammatory diseases. CNS inflammation drives local GDF-1 (...truncated)