COMMENTARY

Time to activin on pathogenic T cells COMMENTARY Anna Eberinga and Ari Waismana,1

Multiple sclerosis (MS) is a demyelinating disease of cytokines they subsequently produce (13). Whereas the central nervous system (CNS) characterized by nonpathogenic Th17 cells that coproduce IL-17 and neuronal and axonal damage resulting in a decline antiinflammatory IL-10 hardly induce EAE when trans- in motor and sensory functions (1). Although the ulti- ferred into mice, pathogenic Th17 cells coexpressing mate cause of the disease has yet to be defined, the IL-17, proinflammatory IFNγ, and granulocyte macro- immune system and, in particular, pathogenic T cells phage colony-stimulating factor (GM-CSF) are associ- play an unarguably important role in disease onset ated with severe EAE outcome (14–16). Strikingly, and progression (2). In PNAS, Morianos et al. extend when Morianos et al. (3) administered activin-A in vivo our knowledge of how pathogenic T cells are regu- to EAE mice, they observed an amelioration of the dis- lated during neuroinflammation (3). ease,withareductioninbothparalysisandlossofmo- Many MS patients develop disease in the form of a tor function. Additionally, they were able to detect + relapsing-remitting MS (RRMS) in early age, of which a decreased frequencies of CD4 TcellsproducingIFNγ, high percentage progress into the primary progres- IL-17, and GM-CSF in the CNS, whereas levels of IL-10− sive form (PPMS). Only a minority of patients develop producing cells were increased. Further, they showed a PPMS form without having been in relapsing- that the treatment of Th17 cells with activin-A orches- remitting state before (4). Relapse and disease pro- trated this alteration in cytokine production through a gression are associated with activated immune cells, set of transcriptions factors, including c-Maf, signal such as plasma cells producing oligoclonal Ig bands transducer and activator of transcription 3 (STAT3), detectable in the cerebrospinal fluid (CSF) or clonally and aryl hydrogen receptor (AhR), binding to promoter + + expanding CD8 T cells as well as cytotoxic CD4 regions of antiinflammatory such as CD39, T cells in active lesions of MS patients (5–8). Interest- CD73, and IL-10, controlling their expression. On the ingly, Morianos et al. (3) find increased levels of the other hand, they found that the proinflammatory tran- cytokine activin-A in the CSF of RRMS patients in the scription factor hypoxia-inducible factor 1-α (Hif1-α)is remitting phase, suggesting a role of this cytokine in retained in the cytoplasm and could hence not initiate modulating the immune response. transcription for the encephalitogenic cytokines MS can be modeled in mice by eliciting a myelin- IL-17, GM-CSF, and IFNγ (Fig. 1). In line with these specific response. This model, termed experi- findings, they find that activin-A serum levels of RRMS mental autoimmune encephalomyelitis (EAE), greatly patients negatively correlate with IL-17 and IFNγ produc- + contributed to our understanding of disease patho- tion by CD4 T cells but, nevertheless, positively corre- + + genicity and uncovered that certain CD4 T cell sub- late with IL-10 production by CD4 Tcells(3). sets, such as interferon γ (IFNγ)-producing T helper Although the etiology of MS has not been fully cells 1 (Th1) and interleukin-17 (IL-17)−producing unraveled yet, studies, nevertheless, have highlighted Th17 cells, are indispensable for disease onset and the importance of Th17 cells and IL-17, showing their progression (9, 10). After their activation, T cells cross correlation with inflammation and disease activity (17). the blood−brain barrier and migrate into the CNS, Dimethyl fumarate has been used in treating RRMS where they are reactivated and subsequently exert their patients because it is believed to reduce the numbers + encephalitogenic functions, feeding a vicious cycle of of IFNγ-producing and IL-17−producing CD4 T cells inflammation (11). Th17 cells were shown to be unsta- and to decrease IL-17 as well as GM-CSF, and there- + ble and can transdifferentiate to Th1 cells (12), but fore highlights the importance of the CD4 Th17 cells they can also be either pathogenic or nonpathogenic, axis in MS (18). Because Th17 cells are very plastic, sev- depending on how they are differentiated and which eral factors, such as melatonin, can impact their functional

aInstitute for Molecular Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz 55131, Germany Author contributions: A.E. and A.W. wrote the paper. The authors declare no competing interest. Published under the PNAS license. See companion article, “Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 and Hif1-α–dependent pathways,” 10.1073/pnas.1918196117. 1To whom correspondence may be addressed. Email: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.2008491117 PNAS Latest Articles | 1of2 Downloaded by guest on September 30, 2021 MS relapsing phase MS reming phase

pathogenic Th17 signature pathogenic Th17 signature acvin-A

ALK4 IL-17 IFN (1) c-Maf AhR STAT3 Hif1-α Hif1-α

(2) (3)

c-Maf AhR STAT3 Hif1-α Entpd1, Nt5e, Il-10 Il-17, Ifn Csf2 (3)

GM-CSF IL-10

Fig. 1. (Left) Activin-A skews encephalitogenic properties of Th17 cells toward an antiinflammatory phenotype. In multiple sclerosis (MS), during disease progression and relapse, Th17 cells produce proinflammatory cytokines interleukin-17 (IL-17), interferon γ (IFNγ), and granulocyte colony-stimulating factor (GM-CSF) regulated via hypoxia-inducible factor 1-α (Hif1-α). (Right) During the remitting phase, increased levels of activin-A act on Th17 cells via receptor ALK4 (1), orchestrating c-Maf, AhR, and STAT3 into the promoter regions of antiinflammatory genes such as CD39, CD73, and IL-10 (2), regulating their expression (3), whereas Hif1-α is being retained in the cytoplasm.

characteristics, inhibiting, for example, their pathogenic potential, remitting RRMS patients and its ability to skew the plasticity of resulting in a decrease in secretion of IFNγ, GM-CSF, and IL-6 and an encephalitogenic Th17 cells toward a nonpathogenic pheno- increase in IL-10 secretion. In line with this, it has been shown that low type, as Morianos et al. (3) report in PNAS. In conclusion, the melatonin levels correlated with longer disease duration (19). frequencies of Th17 cells remain unchanged; however, because Hence, it is not surprising that elevated levels of Th17 cells in of the microenvironment, their functional properties might patients with RRMS have been found, but one is left wondering become antiinflammatory. why no difference in Th17 cell levels between relapsing and remitting patients can be detected (20). Does this phenomenon Acknowledgments stem from the plastic characteristics of Th17 cells shaped by their A.W. is a member of the Center for Immunotherapy and of the Focus Program in microenvironment such as cytokines? Another important ques- Neuroscience of the Johannes Gutenberg University Mainz Research in the A.W. laboratory is supported by grants from the National Multiple Sclerosis Society tion is: What dictates the differentiation of Th17 cells toward a (Grant RG-1707-28780) and from Deutsche Forschungsgemeinschaft Grants nonpathogenic phenotype? Perhaps the answer to these ques- CRC/TRR128 and WA1600/10-1. A.E. is enrolled in the International PhD tions lies partly in the elevated levels of activin-A in the CSF of Program of the Institute for Molecular Biology, Mainz.

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