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Cell-mediated immunity
Published in Gabriel Virella, Medical Immunology, 2019
José C. Crispín, Gabriel Virella
Like CD4 effector cells, CD8 T cells undergo extensive rounds of proliferation following antigen presentation. During their proliferation, they acquire distinct functional characteristics (Table 11.3). They produce high levels of IFN-γ and TNF-α similar to Th1 effector cells. The transcription factors T-bet and eomesodermin control their effector capacities and cytokine production. Most effector CD8 T cells exhibit cytotoxic capability and lyse MHC class I–expressing target cells harboring their specific antigen. Their cytotoxicity is mediated by the presence of perforins and esterases in cytoplasmic granules and by increased expression of membrane-associated Fas ligand.
Pathogenesis of Tuberculosis
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Divya B. Reddy, Jerrold J. Ellner
There is ample evidence that TE, TEM, and TCM can be distinguished from each other biochemically, phenotypically, and functionally. For example, effector and memory T cells generated in response to Listeria infection can be distinguished by the reciprocal expression of the transcription factors T-bet and eomesodermin, respectively.142 Although the underlying mechanisms are not well understood, T effector cells undergo increased apoptosis compared to memory cells. A key difference between TEM and TCM is that TEM migrate to inflamed tissue and have immediate effector function, whereas TCM home to secondary lymphoid organs and have little effector function initially, but rapidly proliferate to become effector cells during a recall response. CD4 TEMs retain their Th1 and Th2 phenotype and rapidly secrete their signature cytokines under appropriate stimulating conditions and CD8 TEMs can be distinguished by their high expression of perforin. Contrarily, TCM, like naïve T cells, requires the appropriate biasing conditions to acquire a Th1 or Th2 phenotype.143 Consistent with this notion, analysis of histone acetylation at promoters of cytokine genes shows that the pattern and level of chromatin remodeling is similar between TEMs and TEs, whereas TCM are more similar to naïve T cells (reviewed in ref.119). Additionally, TCMs are less dependent on co-stimulation for full activation as compared to TEMs. Human TCMs are CD45RO+ and constitutively express CCR7 and CD62L. In contrast, TEMs have lost constitutive expression of CCR7 and express differing levels of CD62L. CD8 effector T cells can be distinguished from T cells by their high expression of CD38, HLA DR, CD27, and Ki-67, and low level expression of BCl-2 and CCR7. Additional memory populations have been defined as stem cell memory, transitional memory, and T-effectory memory reexpressing cells. Memory subsets can be characterized by differential surface expression of CD45RA and CD45RO isotypes, CCR7, CD27, and CD95.144–146
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).
Phenotypic and functional analysis of malignant mesothelioma tumor-infiltrating lymphocytes
Published in OncoImmunology, 2019
Astero Klampatsa, Shaun M. O’Brien, Jeffrey C. Thompson, Abhishek S. Rao, Jason E. Stadanlick, Marina C. Martinez, Maria Liousia, Edward Cantu, Keith Cengel, Edmund K. Moon, Sunil Singhal, Evgeniy B. Eruslanov, Steven M. Albelda
Our Trm findings are similar to those in our recently published early stage lung cancer study, where we saw a similar pattern of response and discovered that the expression of transcription factor Eomesodermin (Eomes) appeared to play a role in downregulating Trm TIL function.15 Eomes is a master transcription factor with context-dependent roles in the effector function of CD8 T cells.42 Its expression in TILs seems to be associated with T cell exhaustion.43 Interestingly, a number of papers have noted that Eomes is normally expressed at only very low levels in Trms.44 When we examined the relationship between the presence of Eomes and IFNγ production in MPM Trms, we found that the CD103+ TILs that did not express Eomes made significantly more IFNγ that the CD103+ cells that did express Eomes. These data support our observations in lung cancer showing an association of Eomes with hypofunction in the generally more active Trm cells within tumors.15
δ-Catenin peptide vaccines repress hepatocellular carcinoma growth via CD8+ T cell activation
Published in OncoImmunology, 2018
Fei Huang, Junying Chen, Ruilong Lan, Zeng Wang, Ruiqing Chen, Jingan Lin, Lurong Zhang, Lengxi Fu
PI3K-Akt signaling and MAPK/ERK signaling have been reported play significant roles in the activation of CD8+ T cells.29,30 We found that in CD8+ T cells, anti-CD3 antibody could stimulate both Akt and ERK signaling. However, δ-Catenin peptides treatment could only stimulate ERK signaling to further activate the differentiation of CTLs both in CD8+ T cells from ICR and C57B/6 mice (Fig 6A-B, 6E-F). T-bet and eomesodermin are the key transcriptional factors for the differentiation of CD8+ T cells to effector or memory T cells.31-33 δ-Catenin peptides treatment could induce the upregulation of both T-bet and Eomes in CD8+ T cells from ICR mice (Fig. 6C-D). However, the peptide vaccines could only upregulate Eomes in CD8+ T cells from C57B/6 mice (Fig. 6G-H). According the results above, δ-Catenin peptides presented to CD8+ T cells, probably activate anti-tumor ability of immune system through activation of ERK signaling and the TF Eomes in CD8+ T cells.
Clinically-Relevant Rapamycin Treatment Regimens Enhance CD8+ Effector Memory T Cell Function In The Skin and Allow their Infiltration into Cutaneous Squamous Cell Carcinoma
Published in OncoImmunology, 2018
Ji-Won Jung, Margaret Veitch, Jennifer A. Bridge, Nana H. Overgaard, Jazmina L. Cruz, Richard Linedale, Michael E. Franklin, Nicholas A. Saunders, Fiona Simpson, Ian H. Frazer, Raymond J. Steptoe, James W. Wells
Our data further suggest that the effects of rapamycin on “memory” cells in the skin are restricted to effector and central, but not resident, memory subsets. Elsewhere, rapamycin has been reported to inhibit the formation of resident memory CD8+ T cells in the intestinal and vaginal mucosa, by inhibiting the formation of resident mucosal memory CD8+ T cell precursors.47 These findings may be explained, at least in part, by the observation that blockade of the mTOR pathway promotes the expression of the T-box transcription factor eomesodermin,25 but near-extinguishment of eomesodermin is necessary for resident memory T cell development.48