TGFβ links EBV to multisystem inflammatory syndrome in children, 2025, Goetzke et al

Abstract

In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock1 termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion2 and systemic hyperinflammation3. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. 4,5). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein–Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.

Conclusion

Here we establish a link between increased TGFβ levels in MIS-C, impaired T cell cytotoxicity and reactivation of EBV. The timing of TGFβ induction before hospital admission remains indeterminable within the scope of this study. For ethical and practical reasons, this question may remain unanswered. Even if TGFβ activation occurs in later stages, prior studies have linked EBV reactivation to increased mortality in critically ill patients53. This underscores the importance of considering TGFβ as a potential treatment target, particularly if its activity is delayed. As MIS-C is rare, age-matched EBV prevalence was calculated with small sample sizes, but the significant increase is unlikely to be due to sampling bias.

Our data suggest that EBV and TGFβ1 have a fundamental role in MIS-C pathogenesis. Increased TGFβ1 levels impair immune cell interactions and T cell cytotoxicity, and limit T cell surveillance of EBV-infected B cells. These mechanisms may contribute to MIS-C hyperinflammation. Targeted TGFβ blockade may help to manage MIS-C and other post-COVID-19 sequelae. Beyond post-COVID-19 sequelae, therapies such as autologous EBV- or SARS-CoV-2-specific T cells engineered to resist TGFβ or immunosuppression58 or antivirals that limit EBV replication could help to alleviate virus-induced hyperinflammation.

https://www.nature.com/articles/s41586-025-08697-6

 

Looks like almost the whole german rheumatology community wrote this (with some LC researchers also included, for example Lael Yonker). Seems significant. Can we now have them working on ME/CFS please?

 

I think there may be something important hiding in all this in relation to TGFbeta but I wish people would just present findings rather than all these interpretative buzzwords. I suspect they have got the causal story back to front but TGF beta may well be key to both LC and ME/CFS.