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Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
PTCL-NOS—PTCL-NOS accounts for around half of the cases of PTCL in Western countries.84,85,106 It is a heterogeneous group of diseases with a predominantly nodal presentation. Genomic characterization of this broad biological group has identified three major subgroups within PTCL-NOS: (i) PTCL-GATA3 which overexpresses GATA3 and has an inferior prognosis, (ii) PTCL-TBX21 which overexpresses TBX21, and (iii) PTCL-TFH which is a nodal PTCL-NOS that expresses a TFH phenotype (CD4+, PD1+, CD10+, BCL6+ CXCL13, and/or ICOS).96 The overall prognosis is variable reflecting the biological heterogeneity of the underlying disorder, ranging from a 5-year OS under 20% in the highest-risk patients to approximately 60% in patients without adverse risk factors.83 Although optimal frontline therapy is unclear, CHOP-type chemotherapy is usually used (with the addition of etoposide possibly adding benefit).90 In addition, there have been attempts to add targeted therapy to CHOP regimens analogous to the addition of rituximab to CHOP in the treatment of B-lineage NHL. CHOP-alemtuzumab,107 CHOP-bortezomib,108 and CHOP-denileukin diftitox109 have all been trialed with varying success. One potential option for CD30-expressing PTCL-NOS is BV-CHP.91
Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Although both the CD8ααTCRαβ+ and the γδTCR+ nIETs depend on strong signals and acquire their activated phenotype “naturally” in the thymus, they follow different pathways. Precursors of the CD8αα+TCRαβ+ nIETs pass through an additional checkpoint that involves the expression of the pre-TCR, and many of these transition to a CD4 and CD8αβ double-positive stage before they undergo the full TCR-based agonist selection process (see Figure 6.4). Also, in vitro differentiation of double-positive thymocytes exposed to their cognate antigen leads to CD8ααTCRαβ+ T cells that express the typical gene transcription profile of CD8ααTCRαβ+ nIETs. Fate-mapping studies, using expression of green fluorescent protein driven by the CD4 promoter, further confirmed that the majority of CD8ααTCRαβ+ nIET progenitors in adult mice transition through the double-positive checkpoint, implying that double-positive thymocytes are heterogeneous and contain precursors for conventional and CD8ααTCRαβ+ T cells. This led to the identification of a new subset of immature thymocytes that coexpress CD8αα together with CD4 and CD8αβ, called triple-positive (TP) cells (see Figure 6.4). Intrathymic injection of TP, but not double-positive, thymocytes led to the generation of CD8ααTCRαβ+ nIETs in vivo, and when exposed to their cognate antigen in vitro, TP thymocytes survived, expanded, and acquired an antigen-experienced phenotype as well as innate-like features and gut-specific homing receptors. These observations further underscore the importance of the thymic agonist selection process as a central mechanism for the unique differentiation and migration of CD8ααTCRαβ+ nIET thymic precursor cells. Agonist-selected TP thymocytes mature to CD5+TCRαβ+ double-negative thymocytes that egress the thymus and directly migrate to the intestinal epithelium (see Figures 6.2 and 6.4). The reexpression of CD8αα and the downregulation of CD5 are postthymic events that occur locally in the intestine and that are actively promoted by IL-15. Similar to TCRγδ+ nIETs, Tbx21 is induced by agonist TCR signals and intestinal IL-15, and this transcription factor is essential for the maturation and maintenance of CD8ααTCRαβ+ nIETs.
Immune Responses Regulated by Exosomal Mechanisms in Cardiovascular Disease
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Brooke Lee, Ioannis D. Kyriazis, Ruturaj Patil, Syed Baseeruddin Alvi, Amit Kumar Rai, Mahmood Khan, Venkata Naga Srikanth Garikipati
The majority of the studies examining miRNA’s role in T-cell functional regulation have involved cancerous diseases. Briefly, EVs derived from nasopharyngeal carcinoma cells possess elevated amounts of miRNA (hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-miR-20a-5p, and hsa-miR-1908), which inhibited T-cell differentiation and proliferation via the MAPK pathway (Ye, Li et al. 2014). This action shifts Th1 and Th17 subtypes into Th2 and Tregs, respectively. Additionally, in mice, lung cancer and sarcomas show that miR-214 drives Treg differentiation through the phosphatase and tensin homolog (Pten) (Walsh, Buckler et al. 2006). Conversely, the lack of miR-155 expression inhibits Treg and Th17 cell development, affecting CD4+-mediated immunosuppression (Chen, Gao et al. 2020). miR-155 has been found to block cellular necrosis post-myocardial injury, further supporting cardiomyocyte survival (Liu, van Mil et al. 2011). miR-142-3p, packaged inside of EVs derived from activated CD4+ T-cells following MI, has been found to deteriorate cardiac remodeling through the molecular fibrosis process via the wingless-related integration site (WNT) pathway (Pontis, Costa et al. 2014). Additionally, a decrease in miR-142-3p exhibited decreased CD4+ T-cell recruitment in atherosclerotic plaque, due to alterations to cytoskeleton dynamics (Pontis, Costa et al. 2014). Furthermore, miR-142-3p upregulation in the exosomes of activated T-cells increases endothelial permeability, which may be implicated in acute cellular rejection in heart transplantations (Sukma Dewi, Celik et al. 2017). Also, miR-29 plays a role in promoting CVD through T-cells. MiR29a-3p and miR-29b-3p can modulate the target genes, T-box transcription factor 21 (Tbx21) and eomesodermin (EOMES). These genes are master transcriptional regulators of CD4+ Th1 cells and can alleviate atherosclerosis development when quenching Th1 progression and stabilizing atherosclerotic plaque (Steiner, Thomas et al. 2011). Conversely, LNA-miR-29 can be administered to silence miR-29 possessing the same qualities by reducing plaque formation (Ulrich, Rotllan et al. 2016). miR-19 is highly expressed during T-cell and B-cell development, promoting lymphocyte survival (Kuo, Wu et al. 2019). Alternatively, it may be a promising target to enhance treatment of an ischemic injury, as it enhances cardiomyocyte proliferation and is found to be upregulated in cardiomyocytes (Gao, Kataoka et al. 2019).
Zinc finger protein 189 promotes the differentiation of lamina propria T helper 17.1 cells in dextran sulfate sodium-induced colitis
Published in Autoimmunity, 2023
Zhihong Xia, Bo Hu, Min Yang, Wenjie He
We aimed to characterise ZFP189 expression in pathogenic Th17 and Th17.1 cells. To this end, we first identified Th17 and Th17.1 cells in CD4+IL-17A+CCR6+ T cells based on the expression of CXCR3 and CCR4. As shown in Figure 2A and B, in the mLNs, about 90% of CD4+IL-17A+CCR6+ T cells were CCR4+CXCR3-/lo and less than 5% were CCR4-/loCXCR3+. In the LP, 70% of CD3+IL-17A+CCR6+ T cells were CCR4+CXCR3-/lo while 25% were CCR4-/loCXCR3+. RORγt protein expression was equivalent in the mLN CCR4+CXCR3-/lo subset, the LP CCR4+CXCR3-/lo subset, and the LP CCR4-/loCXCR3+ subset (Figure 2C and D). RORc mRNA expression was equivalent in the mLN CCR4+CXCR3-/lo subset and CCR4-/loCXCR3+ subset (Supplementary Figure S2). Interestingly, the mLN CCR4+CXCR3-/lo subset and the LP CCR4+CXCR3-/lo subset expressed very low T-bet, whereas the LP CCR4-/loCXCR3+ subset expressed higher T-bet (Figure 2E and F). We found a higher Tbx21 mRNA level in the mLN CCR4-/loCXCR3+ subset relative to the mLN CCR4+CXCR3-/lo subset (Supplementary Figure S2). Therefore, the CCR4+CXCR3-/lo subset contained Th17 cells while the CCR4-/loCXCR3+ subset included Th17.1 cells.
Expression of genes and pathways associated with the B7-CD28 superfamily in response to irradiation of blood cells using 137Cs
Published in International Journal of Radiation Biology, 2021
Daner A. Silveira, Fernanda M. Ribeiro, Éder M. Simão, Viviane L. D. Mattos, Evamberto G. Góes
The pathway of the adaptive immune system showed a significant decrease in relative activity and diversity at 600 cGy. This pathway contains genes related to the adaptive immune response (Pancer and Cooper 2006). Thus, these results suggest that IR can induce an immunosuppressive effect. This suggests that the 600 cGy dose is sufficiently strong to significantly decrease the activity of the immune system. Moreover, the down-regulation of CD28, GATA3, STAT4, and TBX21 observed in our study can contribute to this immunosuppressive effect. CD28 can induce stimulatory signals for the T cell activation through interaction with CD80, CD86, and ICOSLG (Sharpe and Freeman 2002). GATA3, in turn, induces the activation of IL4, which can regulate the differentiation of Th2 cells (Ouyang et al. 1998, 2000; Zhu et al. 2003). STAT4 is also associated with the stimulation of cytokine expressions, such as IFNG in Th1 cells (Frucht et al. 2000; Pearce et al. 2003; Cruz-Guilloty et al. 2009). The down-regulation of TBX21 might indicate the inhibition of the T cell differentiation in Th1 and Th2 (Kanhere et al. 2012). Although we observed the significant decrease of the relative diversity of the adaptive immune system pathway for 150 cGy, this dose does not affect the relative activity, which is associated with the pathway activation.
Emerging roles of noncoding RNAs in T cell differentiation and functions in autoimmune diseases
Published in International Reviews of Immunology, 2019
Naïve CD4+ T cells differentiate into Th1 cells in the presence of IL-12/IFN-γ, expresses Tbx21 which transactivates Ifng gene and promote Th1 developmental program. In a mutually exclusive manner, Th1-associated factors, IL-12, IFN-γ and Tbet, suppress Th2 differentiation by inhibiting GATA-3 functions [26]. It was identified that lncRNA, Linc-MAF-4 expression reciprocally regulates Th1 and Th2 differentiation [27], by inducing Th1 cells differentiation and functions. Further analysis of Linc-MAF-4 revealed that it promotes Th1 cells differentiation by repressing the transcription of MAF-4, a Th2-associated transcription factor [27]. Molecularly, Linc-MAF-4 recruits chromatin modifiers EZH2 and LSD1 at MAF-4 promoter to repress its transcription (Figure 1), as inhibition of Linc-MAF-4 rescued Th2 differentiation via MAF-4 activation [27].