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CD4+ helper T cells are crucial for the adaptive immune response. Traditionally, these cells differentiate from naïve cells into effector/memory cells upon recognition of foreign antigens. However, recent evidence suggests that naïve CD4+T cells can also spontaneously acquire a memory phenotype (MP) in the steady state, presumably through self-antigen recognition, leading to the generation of MP T cells. These MP cells are maintained by rapid proliferation in the periphery and can differentiate into T-bet-expressing 'MP1' cells, which can exert innate effector functions, such as producing IFNγ in response to IL-12 without antigen recognition. This study aims to further understand the heterogeneity and functional significance of MP CD4+ T lymphocytes, particularly the T-bet- Rorγt- subpopulation, which remains less understood.
The first set of experiments aimed to understand the accumulation of MP cells in the absence of a functional adaptive immune system. The researchers used Rag2−/− mice to investigate the spontaneous accumulation of self-reactive MP cells in multiple organs. The results showed a significant accumulation of these cells, indicating that MP cells can proliferate and accumulate in the periphery even without foreign antigen stimulation. By sorting T-bet-Rorγt- and T-bet+Rorγt- MP cells from T-bet/Rorγt/Foxp3 reporter mice and transferring them into Rag2−/− hosts, the researchers observed that the undifferentiated MP cells could give rise to T-bet+, Rorγt+, and Foxp3+ subsets. This demonstrated the plasticity of these cells and their ability to differentiate into various T cell lineages. They further investigated the transcriptional profile of MP cells, revealing their immature state and poly-clonality. This was evidenced by the presence of a broad range of TCR clonotypes among the T-bet− MP, T-bet+ MP, and pTreg cells. The data suggested that MP cells maintain a diverse repertoire, which is crucial for their ability to respond to various antigens and environmental cues. T-bet-Rorγt- MP, T-bet+Rorγt- MP, and naïve cells were transferred into congenic Foxp3-DTR mice, and subsequent analysis showed that the undifferentiated MP cells rapidly proliferated and differentiated into TH1/17/Treg cells upon stimulation. This highlighted the responsiveness of these cells to inflammatory signals and their role in immune responses. The research revealed that the differentiation of MP cells into effector T cells is regulated by preexisting Treg cells. By using Foxp3-DTR mice and subjecting them to DT treatment, the researchers observed that the response of undifferentiated MP cells was tonically constrained by Treg cells. This finding underscores the importance of Treg cells in maintaining immune homeostasis and preventing excessive inflammation. Finally, they addressed the contribution of MP cells to the pathogenesis of inflammation. The data argued that while the T-bet+ Rorγt- MP subset is terminally TH1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate and differentiate into TH1/17/Treg cells, contributing to mild and persistent inflammation in lymphopenic environments. In conclusion, this article provides a detailed characterization of naturally arising memory-phenotype CD4+ T lymphocytes, emphasizing their undifferentiated population's ability to generate various T cell subsets and their role in immune responses and inflammation. These findings advance the understanding of CD4+ T cell biology and have implications for the development of therapeutic strategies targeting immune-mediated diseases.
DOI: 10.1126/sciadv.adq6618
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The role of ICOS in overall antitumor immune responses remains controversial. It has been shown that tumor vaccines engineered to express ICOSL boost vaccine efficacy, suggesting that ICOS co-stimulation has a dominant effect in supporting antitumor immunity. In contrast, high levels of ICOSL expression in the tumor microenvironment appear to favor protumor roles by increasing Treg cell responses. Thus, more work is required to fully understand the dual role of ICOS in antitumor immune responses. This is particularly important because there are ongoing clinical trials testing agonistic or antagonistic ICOS Abs.
In this study, they monitored tumor growth in mice lacking ICOS either in all the T cell compartments or selectively in Treg cells.Firstly, they compared tumor progression in mice with selective ICOS deficiency in Treg cells versus all T cells, using an experimental melanoma lung metastasis model. The results show that Treg cell-specific ICOS knockout (KO) reduces overall tumor burden compared to Cre control mice, with increased CD4+-to-Treg cell and CD8+-to-Treg cell ratios in the tumor. This suggests that ICOS on Treg cells plays a role in promoting tumor progression. Mice lacking ICOS in all T cell compartments did not show differences in tumor burden, indicating that the absence of ICOS on Treg cells specifically influences tumor growth. Consistent with the reduced tumor burden observed in Treg cell-specific ICOS KO mice, there is an increase in CD8+ CTLs that express high levels of granzyme B and perforin. These molecules are crucial for the cytotoxic activity of CTLs, suggesting that ICOS-expressing Treg cells may suppress the development of effective antitumor CTL responses. Single-cell transcriptome analysis provides further insights into the composition of CD8+ T cells in Treg cell-specific ICOS KO mice. There was an increase in Ly108+EomeshiCD8+ T cells at the expense of the Ly108+T-bethi subset. This suggests that ICOS-expressing Treg cells suppress the maturation of CTLs, particularly at the level of Eomes upregulation, which is a critical step in driving perforin expression and cytotoxicity.The data imply that cancer immunotherapies using ICOS agonist antibodies may be more effective in tumors with low Treg cell infiltration or when combined with treatments that deplete tumor-infiltrating Treg cells. This highlights the potential of targeting ICOS-expressing Treg cells to enhance the efficacy of immunotherapies. And the chemokine CCL20, secreted by hepatocellular carcinoma (HCC) cells, may contribute to the enrichment of Tregs in tumor tissues. This finding points to a potential pathway for the selective migration of Treg cells to tumors, which could be targeted therapeutically.
DOI: 10.4049/jimmunol.2300154
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