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• FOXP3 controls Treg differentiation and activity. • FOXP3 induces metabolic versatility in intra-tumoral Tregs. • Treg subsets show different reliance on FOXP3. Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens–associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper. [ABSTRACT FROM AUTHOR]

CD28 and CD80/86 are crucial co-stimulatory molecules for the T cell activation. Previous study illustrated that CD28 and CD80/86 present on T cells and antigen-presenting cells in flounder (Paralichthys olivaceus), respectively. The co-stimulatory molecules were closely associated with cell immunity. In this paper, recombinant protein of flounder CD80/86 (rCD80/86) and phytohemagglutinin (PHA) were added to peripheral blood leukocytes (PBLs) in vitro. Lymphocytes were significantly proliferated with CFSE staining, and the proportion of CD4+ and CD28+ lymphocytes significantly increased. In the meantime, genes related to the CD28-CD80/86 signaling pathway or T cell markers were significantly upregulated (p < 0.05). For further study, the interaction between CD80/86 and CD28 was confirmed. The plasmid of CD28 (pCD28-FLAG and pVN-CD28) or CD80/86 (pVC-CD80/86) was successfully constructed. In addition, pVN-ΔCD28 without the conserved motif "TFPPPF" was constructed. The results showed that bands of pCD28-FLAG bound to rCD80/86 were detected by both anti-FLAG and anti-CD80/86. pVN-CD28 complemented to pVC-CD80/86 showing positive fluorescent signals, and pVN-ΔCD28 failed to combine with pVC-CD80/86. The motif "TFPPPF" in CD28 played a crucial role in this linkage. These results indicate that CD28 and CD80/86 molecules interact with each other, and their binding may modulate T lymphocytes immune response in flounder. This study proved the existence of CD28-CD80/86 signaling pathway in flounder. • RCD80/86 and PHA induced lymphocyte proliferation and proportion of CD4+ cells in flounder. • RCD80/86 and PHA upregulated the expression of B7-CD28 signaling pathway genes, T cell markers, and cytokines. • PCD28-FLAG bound to rCD80/86, and pVN-CD28 complemented to pVC-CD80/86 in vitro. • Motif of "TFPPPF" in CD28 plays crucial role in the interaction between CD28 and CD80/86. [ABSTRACT FROM AUTHOR]

Interleukin-2 receptor (IL-2R), as the specific ligand of interleukin-2 (IL-2), binds to IL-2 and transmits signals and then can induce the proliferation of T lymphocytes in mammals. In this paper, the subunit of IL-2R in flounder (Paralichthys olivaceus), interleukin-2 receptor subunit gamma (IL-2Rγ) was cloned, and polyclonal antibodies (Abs) against its extracellular region were produced, then the expression of flounder IL-2Rγ (fIL-2Rγ) at transcriptional and cellular levels were characterized. Moreover, the interaction of flounder IL-2 (fIL-2) with fIL-2Rγ was investigated, and the variations on CD4+/IL-2Rγ+ cells in flounder after treatment with recombinant IL-2 (rIL-2), anti-IL-2Rγ Abs were detected, respectively. The results showed that fIL-2Rγ protein had a typical fibronectin type III (FN3) domain. The Abs could specifically recognize native fIL-2Rγ molecules at 39.9 kDa. FIL-2Rγ was localized on both T and B lymphocytes, and the percentages of CD4+/IL-2Rγ+ and IgM+/IL-2Rγ+ lymphocytes were high in spleen. In addition, pBiFC-VN173-IL-2Rγ plasmids could bind to pBiFC-VC155-IL-2 plasmids. The percentage of CD4+/IL-2Rγ+ lymphocytes was significantly decreased after blocking with anti-IL-2Rγ Abs both in vivo and in vitro. In the meantime, four T cell markers genes and six IL-2-IL-2R pathway genes were down-regulated in anti-IL-2Rγ Abs group. These results first demonstrated that fIL-2Rγ molecules were expressed on both T and B lymphocytes in flounder, and the bond between fIL-2Rγ and fIL-2 activated the CD4 T lymphocytes. This study gave a new sight into the exploration of IL-2R function on T lymphocytes proliferation in fish. • IL-2Rγ mRNA was highly expressed in peripheral blood leukocytes, spleen and head kidney in flounder. • IL-2Rγ molecules were localized on both T and B lymphocytes in flounder. • Flounder IL-2 could bind to flounder IL-2Rγ. • The addition of recombinant IL-2 significantly increased the percentage of CD4+/IL-2Rγ+ lymphocytes at 72 h. [ABSTRACT FROM AUTHOR]

Immunological memory can be regarded as the key aspect of adaptive immunity, i.e. a specific response to first contact with an antigen, which in mammals is determined by the properties of T, B and NK cells. Re-exposure to the same antigen results in a more rapid response of the activated specific cells, which have a unique property that is the immunological memory acquired upon first contact with the antigen. Such a state of immune activity is also to be understood as related to "altered behavior of the immune system" due to genetic alterations, presumably maintained independently of the antigen. It also indicates a possible alternative mechanism of maintaining the immune state at a low level of the immune response, "directed" by an antigen or dependent on an antigen, associated with repeated exposure to the same antigen from time to time, as well as the concept of innate immune memory, associated with epigenetic reprogramming of myeloid cells, i.e. macrophages and NK cells. Studies on Teleostei have provided evidence for the presence of immunological memory determined by T and B cells and a secondary response stronger than the primary response. Research has also demonstrated that in these animals macrophages and NK-like cells (similar to mammalian NK cells) are able to respond when re-exposed to the same antigen. Regardless of previous reports on immunological memory in teleost fish, many reactions and mechanisms related to this ability require further investigation. The very nature of immunological memory and the activity of cells involved in this process, in particular macrophages and NK-like cells, need to be explained. This paper presents problems associated with adaptive and innate immune memory in teleost fish and characteristics of cells associated with this ability. • The presence of adaptive and innate immune memory has been confirmed in fish. • Adaptive immune memory in fish develops with the participation of T and B lymphocytes. • Innate immune memory is related to the properties of macrophages and NK-like cells. • There is a need to further verify the biological basis of this property. [ABSTRACT FROM AUTHOR]

• A model is proposed based on the key role of Regulatory T cells in chemoimmunotherapy. • The model's fixed points are obtained and the bifurcation diagrams are discussed. • New features of personalizing a cancer mathematical model are presented. • Considering Regulatory T cells leads to identifying critical patient conditions more precisely. Studying the mathematical dynamics of cancer has gained the attention of bioengineers in the past three decades. Different kinds of modelling considering various aspects of treatment have been proposed. In this paper, the key role of Regulatory T cells is discussed and a model in ordinary differential equation (ODE) form is proposed by adding this state to the system dynamics considering chemoimmunotherapy treatment. Regulatory T cells are considered as one of the main tumor cells' tactics to deceive the body's immune system. The improved model is verified mathematically and biologically and fits all criteria in both fields. The results show that entering Regulatory T cells state on cancer mathematical modelling for simulating body cells for chemoimmunotherapy provides a way to identify critical cases more carefully, which a simplified model is unable to accomplish. This point emphasizes the fact that this state must be present in cancer modelling to anticipate immune response more accurately. The advanced system fixed points are obtained by the Newton method and bifurcation diagrams are derived and discussed. New features and remarks are proposed during the journey of developing more accurate models that have the best fit with laboratory data. The sensitivity chart of the model is illustrated and novel aspects of discussions are made with the aim of personalizing a model for a patient and identifying critical conditions based on the chart before any treatment begins. This point enables physicians to determine whether critical conditions have occurred for a patient in a specific treatment or not. [ABSTRACT FROM AUTHOR]

Various categories of coronavirus disease 19 (COVID-19) patients have exhibited major mortality rate differences and symptoms. Some papers have recently explained these differences in mortality rates and symptoms as a consequence of this virus infection acting in synergy with one or more latent pathogen infections in some patients. A latent pathogen infection likely to be involved in millions of these patients is the protozoan parasite Toxoplasma gondii , which infects approximately one third of the global human population. However, other papers have concluded that latent protozoan parasite infections can reduce the severity of viral infections. The aims and purposes of this paper include providing explanations for the contradictions between these studies and introducing a significant new category of T-cell exhaustion. Latent pathogens can have different genetic strains with great differences in their effects on a second pathogen infection. Furthermore, depending on the timing and effectiveness of drug treatments, pathogen infections that become latent may or may not later induce immune cell dysfunctions, including T-cell exhaustion. Concurrent multiple pathogen T-cell exhaustion is herein called "polyspecific T-cell exhaustion." • COVID-19 patients exhibit mortality rate differences probably from latent pathogen infections. • Toxoplasma gondii infects about one third of the global human population and it is likely involved. • Latent pathogens have different genetic strains & different effects on later pathogen infections. • Drug treatments affect pathogen infections causing immune dysfunctions, e.g. T-cell exhaustion. • "Polyspecific T-cell exhaustion" enables concurrent multiple pathogen T-cell exhaustion. [ABSTRACT FROM AUTHOR]

The newly discovered subset of memory T cells, tissue resident memory T (TRM) cells, reside in peripheral tissues for a long time, contributing to a rapid immune response and constituting the first line of defense when pathogens invade cells. Tissue resident memory T cells have unique transcriptome characteristics, and their presence in peripheral tissues is regulated by many factors. TRM cells residing in different tissues often express different surface markers. In addition to CD8+ and CD4+ T cells, which are the best-characterized T cells, Treg cells and various innate T cells can reside in nonlymphoid tissues. Many recent studies have shown that tissue resident memory T cells play indispensable roles in tumor immunity and allergic diseases. This paper reviews the differentiation, regulation, variety and function of TRM cells and the roles they play in skin diseases, including cutaneous melanoma and psoriasis. • Tissue-resident memory T cells exhibit distinct tissue-specific and niche-specific functions in immune detection network. • Multiple factors control the development and resident of Tissue-resident memory T cell. • Tissue-resident memory T cells participate in skin inflammation and contribute tomaintaining the recurrence of skin diseases. [ABSTRACT FROM AUTHOR]

Psoriasis is a common inflammatory skin disease involving interactions between keratinocytes and immune cells that significantly affects the quality of life. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes and excessive infiltration of immune cells in the dermis and epidermis. The immune mechanism underlying this disease has been elucidated in the past few years. Research shows that psoriasis is regulated by the complex interactions among immune cells, such as keratinocytes, dendritic cells, T lymphocytes, neutrophils, macrophages, natural killer cells, mast cells, and other immune cells. An increasing number of signaling pathways have been found to be involved in the pathogenesis of psoriasis, which has prompted the search for new treatment targets. In the past decades, studies on the pathogenesis of psoriasis have focused on the development of targeted and highly effective therapies. In this review, we have discussed the relationship between various types of immune cells and psoriasis and summarized the major signaling pathways involved in the pathogenesis of psoriasis, including the PI3K/AKT/mTOR, JAK-STAT, JNK, and WNT pathways. In addition, we have discussed the results of the latest omics research on psoriasis and the epigenetics of the disease, which provide insights regarding its pathogenesis and therapeutic prospects; we have also summarized its treatment strategies and observations of clinical trials. In this paper, the various aspects of psoriasis are described in detail, and the limitations of the current treatment methods are emphasized. It is necessary to improve and innovate treatment methods from the molecular level of pathogenesis, and further provide new ideas for the treatment and research of psoriasis. • The relationship between various immune cells and psoriasis is discussed. • Major signaling pathways involved in the pathogenesis of psoriasis are summarized. • Results of the latest omics research on psoriasis are discussed. • Treatment strategies and clinical trial observations for psoriasis are summarized. [ABSTRACT FROM AUTHOR]

• An individual-based model describing interactions between tumour and CD8+ T cells. • The model takes into account tumour antigen expression and presentation. • The degree of tumour heterogeneity has an impact on immune response efficacy. • Wider ranges of antigens promote immune escape of tumours. • Lower levels of antigen presentation diminish the immune action. Intra-tumour heterogeneity (ITH) has a strong impact on the efficacy of the immune response against solid tumours. The number of sub-populations of cancer cells expressing different antigens and the percentage of immunogenic cells (i.e. tumour cells that are effectively targeted by immune cells) in a tumour are both expressions of ITH. Here, we present a spatially explicit stochastic individual-based model of the interaction dynamics between tumour cells and CD8+ T cells, which makes it possible to dissect out the specific impact of these two expressions of ITH on anti-tumour immune response. The set-up of numerical simulations of the model is defined so as to mimic scenarios considered in previous experimental studies. Moreover, the ability of the model to qualitatively reproduce experimental observations of successful and unsuccessful immune surveillance is demonstrated. First, the results of numerical simulations of this model indicate that the presence of a larger number of sub-populations of tumour cells that express different antigens is associated with a reduced ability of CD8+ T cells to mount an effective anti-tumour immune response. Secondly, the presence of a larger percentage of tumour cells that are not effectively targeted by CD8+ T cells may reduce the effectiveness of anti-tumour immunity. Ultimately, the mathematical model presented in this paper may provide a framework to help biologists and clinicians to better understand the mechanisms that are responsible for the emergence of different outcomes of immunotherapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is classified as the third leading cancer globally and one of the major causes of morbidity and mortality around the world. The interaction of the immune system with the cancer cells plays a vital role in CRC progression. Regulatory T cells (Tregs) are a form of T cells, which regulate and suppress unwanted activation of the immune system and play a major role in preventing autoimmune diseases. Tregs exhibit a significant role in immune modulation during CRC progression through accumulation in the tumor microenvironment (TME) and suppression of immunity against tumor specific antigens promoting tumor progression. The role of Tregs in CRC progression and its interaction with other immune cells within CRC TME and current clinical trials were reviewed in this paper. [Display omitted] • Discusses the role of Tregs in immune modulation during CRC progression. • Explores the role of Tregs in CRC tumor microenvironment. • Highlights the mechanism of Tregs in CRC growth and metastasis. • Identifies and discusses current clinical trials targeting Tregs in CRC therapy. [ABSTRACT FROM AUTHOR]