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Eomesodermin+ CD4 T cells are critical for curative immunotherapy outcomes

ABSTRACT: IL-10-producing CD4+ type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomes-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT) and chimeric antigen receptor (CAR) T cell immunotherapy, we demonstrate a Tr1 differentiation trajectory in vivo from Eomes+IL-10– to Eomes+IL-10+ subsets with the acquisition of cytokine, cytolytic and exhaustion features. The Eomes+CD4+ fraction represents the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted CAR T cell immunotherapy, Eomes drives the same CD4+ Tr1 phenotype that controls cytolysis, whilst mitigating immune toxicity and promoting persistence. In patients receiving commercial CD19-targeted CAR T cells with long term disease control, Eomes+ Tr1 cells represent a stable population comprising 40-80% of the CD4+ CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4+ T cells, essential for curative immunotherapy outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE305624 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Dengue virus (DENV) infection is associated with a range of clinical manifestations, from self-limiting dengue fever (DF) to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Although DENV-specific CD4 T cells are capable of producing inflammatory cytokines and can acquire cytotoxic functions in previously DENV-exposed individuals, much less is known related to DENV-specific CD4 T cells during acute DENV infection and disease. In this study, we set out to characterize the immune signatures of DENV-specific CD4 T cells during acute infection and investigate whether DENV-specific CD4 T cell response differs between DF and DHF. Previous studies suggest that increased IL-10 level in the blood is associated with severe dengue disease. Here we show evidence of DENV-specific IL-10-producing CD4 T cells during acute DENV infection. More specifically, an IL-10+IFN-γ+ double positive (DP) CD4 T cell population was prominent in acute hospitalized DENV cases but disappeared at the convalescent stage. RNA-sequencing analysis revealed that these cells were associated with gene signatures that marginally overlapped with previously identified signatures of cytotoxic CD4 T cells and type 1 regulatory T (Tr1)-like cells. However, the majority of the genes differentially expressed by DP cells were not related to cytotoxic CD4 T cells or Tr1-like cells. These genes include IL-21, IL-22, CD86, CD109, and CCR1, which are involved in T cell activation, function, cytokine signaling, and migration. Notably, the magnitude of DP cell response was higher in DHF than DF, whereas the gene expression profile of DP cells was similar between DF and DHF. Finally, our data show that DENV-specific DP cells are largely homogeneous based on the expression of 31 selected markers. Overall, this study reveals unique phenotypes of virus-specific IL-10/IFN-γ co-producing CD4 cells and indicates that the quantity but not quality of these cells may be positively correlated with dengue disease severity.

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Eomesodermin+ CD4 T cells are critical for curative immunotherapy outcomes

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