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For decades, the Th1/2 paradigm has been used to classify immune responses as either Th1 or Th2-biased. However, in recent years, a staggering amount of evidence has emerged to support rejection of the classical Th1/Th2 paradigm, such as the discoveries of new helper T cell subsets, helper T cell plasticity and protective mixed-Th1/Th2 responses. This opinion piece investigates the shortcomings of classical Th1/Th2 paradigm in the context of recent works, with the goal of facilitating the development of newer models to represent the diversity of Th cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The synovial fluid (SF) microenvironment in rheumatoid arthritis (RA) may alter the stability and function of Tregs. In the present study, we assessed cytokine levels and percentage of Tregs, Tregs expressing CXCR3 (Th1-like Treg), CCR6 (Th17-like Treg) in RA peripheral blood (PB) and RA-SF using fluorescence cytometry. Effect of autologous SF on plasticity and function of RA-PB Tregs (pTregs; CD4 + CD25 hi CD127 Lo/- ) and induced vimentin-pulsed Tregs (iTregs VIM ) was assessed in vitro. Cytokines and percentage of Th1-like and Th17-like Tregs were higher in RA-PB than OA-PB; higher in RA-SF than osteoarthritis (OA)-SF. Compared to OA-SF exposed OA-pTregs, RA-SF exposed RA-pTregs showed higher percentage of Th1-like (11% vs 20%) and Th17-like (16% vs 36%) Tregs; higher T-bet (p = 0.0001), RORγ (p = 0.0001) and lower FOXP3 (p = 0.0001) gene expression; and diminished percentage suppression of autologous T effector cells (36% vs 74%). RA-SF exposed iTregs VIM showed increased percentage of Th1-like and Th17-like Tregs compared to iTregs VIM exposed to AB serum (8% vs 0.1%; 21% vs 0.1%). IL-2, Tocilizumab and 5-azacytidine reduced the conversion of iTregs VIM (8% vs 2.4%; 21% vs 6.9%), when used in combination. To conclude, microenvironment in the RA synovial fluid is possibly responsible for conversion of pTregs into Th-like Tregs and their functional loss. A blockade of cytokine receptors and methyl transferases could inhibit Tregs conversion, providing clinical relevance for future Tregs targeting therapies., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interests., (Copyright © 2024 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Master CD4 + T cell lineage determined transcription factors are found to be dysregulated in pathogenesis of autoimmune and inflammatory diseases. CD4 + T cells categorized into different lineages based on their functions, cell surface markers and master transcription factors those required for expression of lineage specific cytokines. T-bet, GATA3, RORγt and Foxp3 are major transcription regulators of Th1, Th2, Th17 and Treg cells respectively. Significant progress has been made in understanding expression of lineage specific master regulators that drives CD4 + T cell differentiation. It is known that each CD4 + T cell lineage express precise determined transcription factor and due to cross regulation between these factors the CD4 + T cells able to maintain thier specific phenotype. However, recent studies shows that the lineage specifying transcription factors frequently co-expressed. There is an emerging area of research revealing that the co-expression of lineage-specifying transcription factors alters the potential function and flexibility of subsets of CD4 + T cell, this in turn favors the autoimmune pathology. Here, we discuss similarities and differences between mutually co-expressed transcription factors in CD4 + T cell subsets and then recapitulates on cell type specific and dynamic balance between the lineage restricted transcription factors in determining plasticity of CD4 + T cell subsets. Furthermore, we discuss abnormal regulation of such transcription factors that establishes a pathogenic CD4 + T cell phenotype in autoimmune diseases and how this understanding will provide further insight into potential therapeutic development., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Interleukin (IL)-33 is an alarmin factor that is highly secreted in a variety of autoimmune diseases, induces maturation of dendritic cells (DCs) and differentiation of T helper 17 (Th17) cells. As the balance between Th17 cells and regulatory T cells (Tregs) is important to maintain immune homeostasis, in this study, we investigated the effects of IL-33 on Treg cell response. We observed that direct treatment with IL-33 had no effect on Treg differentiation, whereas IL-33-matured DCs (IL33-matDCs) inhibited the differentiation of CD4 + T cells to Tregs by decreasing the expression of Foxp3. Furthermore, co-culture with IL-33-matDCs changed stable Tregs (CD25 hi CD4 + Tregs) to IL-17-producing cells, whereas IL-33-matDCs had little effects on unstable Tregs (CD25 lo CD4 + Tregs). The stable Tregs were demonstrated to express high levels of IL-6 receptors. Blocking of IL-6 secreted from IL-33-matDCs suppressed the conversion of Tregs to Th17 cells, indicating the greater propensity to convert stable Tregs to Th17 cells is due to IL-6 signaling. Taken together, these results demonstrate that IL-33 inhibits Treg differentiation and the conversion of stable Tregs to Th17 cells via DCs., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest regarding the publication of this paper., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Mast cells (MCs), a type of innate immune cells, are derived from myeloid stem cells, sometimes known as mastocytes or labrocytes, and contain many granules rich in histamine and heparin. The mentioned cells are able to release various mediators such as cytokines, leukotrienes, and a large number of proteases into the environment. Many studies and experiments have established the infiltration of MCs into the tumor site. However, the findings are highly controversial to determine whether these immune cells contribute to the growth and development of the tumor or cause anti-tumor immune responses. Various studies have revealed that MCs have a pro-tumorigenic or anti-tumorigenic role depending on the type of cancer, the degree of tumor progression, and the location of these immune cells in the tumor bulk. Although these types of immune cells cause angiogenesis and tumor progression in some cancers, they have a significant anti-tumor role in some other types of cancers. In general, although a number of studies have specified the protective role of MCs in cancers, the increased number of MCs in the blood and microenvironment of tumors, as well as the increased level of angiogenesis and tumor progression, has been indicated in another array of studies. The function of MCs against or in favor of the cancers still requires further investigations to more accurately and specifically determine the role of MCs in the cancers. The function of MCs in tumors and their various roles in case of exposure to the cancer cells have been addressed in the present review. The concluding section of the present study recommends a number of methods for modification of MCs in cancer immunotherapy., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Innate lymphoid cells (ILCs) are a heterogeneous population of cells with diverse roles in immune responses. Three major groups of ILCs have been defined on the basis of similarity in their production of signature cytokines, developmental requirements, and phenotypic markers. Group 1 ILCs produce IFN-γ, express the T-box transcription factors (TF) T-bet and/or Eomesodermin (Eomes), group 2 ILCs secrete IL-5 and IL-13 and express the TF GATA-3, while group 3 ILCs produce IL-22 and IL-17 and express the TF RORgt. In this review, we will briefly overview each group in terms of phenotype, function and development and then focus more extensively on group 1 ILCs, expanding on their emerging diversity, their disparate functions and the differences between NK cells and ILC1., (Copyright © 2016. Published by Elsevier B.V.)

Group 2 innate lymphoid cells (ILC2) are specialized in type 2 immunity. ILC2 are activated early in immune responses and, despite their low abundance, are able to initiate and amplify allergic inflammation by orchestrating other type 2 immune cells. Based on recent discoveries, the spectrum of ILC2 regulating factors has been extended. It is now well established that not only epithelial cell-derived innate cytokines, but also bioactive lipids can regulate ILC2 activity and accumulation. Additionally, ILC2 appear to be susceptible to changes in the cytokine milieu and can acquire an ILC1-like phenotype due to a high degree of cellular plasticity. As ILC2 are fundamentally involved in the pathogenesis of type 2 diseases, they represent a promising therapeutic target for allergic airway and skin diseases. In this review we summarize the current knowledge about ILC2 biology in the allergy context, with a particular focus on the emerging role of lipid mediators in regulating ILC2 function., (Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.)