Abstract:Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T ce… Show more
“…The number of T cells obtained per mm 3 was significantly higher in transplantectomy tissue (which is not unsurprising given the inflammatory conditions of these kidneys) [38], but the differences (before and after culture) in T cell subset composition, cytokine expression profiles, transcription factors and tissue culture characteristics were relatively minimal to modest. This unexpected finding was also reported in a recent study by van der Putten et al [33] and indicates that other data are needed, e.g., determination of antigen-specificity, studies on control mechanisms of effector functions or T cell metabolic state [39], to assess whether the tissue-resident T cells are active and deleterious or in a resting state.…”
Studying functionality and antigen-specificity of resident kidney T cells derived from a kidney biopsy is hampered by the lack of sufficient numbers of T cells obtained by the standard method of enzymatic tissue dissociation. Enzymatic dissociation of kidney tissue was compared to a novel method of whole kidney tissue culture allowing T cells to migrate into the medium in the presence of exogenous IL-2 and IL-15. T cell numbers were quantified and phenotype of resident T cells (CD69+CD103+/−), TCR Vβ repertoire and functional characteristics were analyzed with multi-parameter flow cytometry. Renal tissue culture for four weeks in the presence of exogenous IL-2 and IL-15 yielded significantly higher numbers of T cells (1.3 × 104/mm3) when compared to cultures without exogenous cytokines (71/mm3) or direct isolation by enzymatic dissociation (662/mm3 T cells, p < 0.05). The proportion of T cells with a resident phenotype did not change in the tissue culture; percentages amounted to 87.2% and 85.1%, respectively. In addition, frequencies of CD4+, CD8+, CD4−CD8−, T cells and MAIT T cells remained similar. For both CD4+ and CD8+, T cells had a more differentiated memory phenotype after tissue culture, but the distribution of TCR Vβ families did not change. In addition, the predominant Th1 cytokine secretion profile and poly-functionality of resident kidney T cell remained intact. T cell proliferation potential was not affected, excluding exhaustion and enrichment of BKV- and CMV-reactive resident T cells was observed. In conclusion, the kidney tissue culture method yields significantly increased numbers of resident T cells without major effects on composition and functionality.
“…The number of T cells obtained per mm 3 was significantly higher in transplantectomy tissue (which is not unsurprising given the inflammatory conditions of these kidneys) [38], but the differences (before and after culture) in T cell subset composition, cytokine expression profiles, transcription factors and tissue culture characteristics were relatively minimal to modest. This unexpected finding was also reported in a recent study by van der Putten et al [33] and indicates that other data are needed, e.g., determination of antigen-specificity, studies on control mechanisms of effector functions or T cell metabolic state [39], to assess whether the tissue-resident T cells are active and deleterious or in a resting state.…”
Studying functionality and antigen-specificity of resident kidney T cells derived from a kidney biopsy is hampered by the lack of sufficient numbers of T cells obtained by the standard method of enzymatic tissue dissociation. Enzymatic dissociation of kidney tissue was compared to a novel method of whole kidney tissue culture allowing T cells to migrate into the medium in the presence of exogenous IL-2 and IL-15. T cell numbers were quantified and phenotype of resident T cells (CD69+CD103+/−), TCR Vβ repertoire and functional characteristics were analyzed with multi-parameter flow cytometry. Renal tissue culture for four weeks in the presence of exogenous IL-2 and IL-15 yielded significantly higher numbers of T cells (1.3 × 104/mm3) when compared to cultures without exogenous cytokines (71/mm3) or direct isolation by enzymatic dissociation (662/mm3 T cells, p < 0.05). The proportion of T cells with a resident phenotype did not change in the tissue culture; percentages amounted to 87.2% and 85.1%, respectively. In addition, frequencies of CD4+, CD8+, CD4−CD8−, T cells and MAIT T cells remained similar. For both CD4+ and CD8+, T cells had a more differentiated memory phenotype after tissue culture, but the distribution of TCR Vβ families did not change. In addition, the predominant Th1 cytokine secretion profile and poly-functionality of resident kidney T cell remained intact. T cell proliferation potential was not affected, excluding exhaustion and enrichment of BKV- and CMV-reactive resident T cells was observed. In conclusion, the kidney tissue culture method yields significantly increased numbers of resident T cells without major effects on composition and functionality.
“…An increase in SRC is a character of energy metabolism in the memory T cells and in GR is a feature of the effector T cells. 27 , 28 The data suggest that glucose metabolism is reprogrammed in the KO cells for enhanced glycolysis and decreased OXPHOS. Figure 3.…”
ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F
1
F
o
-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8
+
T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8
+
T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8
+
T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.
“…Persistent stimulation of T cells, often seen in T cells infiltrating tumours, can lead to T cell exhaustion, with T cells no longer able to respond to stimuli. Recent research has shown that mitochondria play distinctive roles, adopting different morphologies and functions, in each of these different T cell subsets [4]. This makes T cells a particularly interesting cell type in which to uncover the multiple roles of mitochondria.…”
Section: Changing Requirements For Mitochondria Through T Cell Develo...mentioning
confidence: 99%
“…for oxidative phosphorylation (OXPHOS) than smaller mitochondria (resulting from fission). While naïve T cells have little mitochondrial mass, effector CTLs have fragmented mitochondria, and memory cells show more elongated mitochondria [4]. Reshaping mitochondria is important for T cell development, as demonstrated by the disrupted development of naïve T cells after deletion of genes encoding proteins required for mitochondrial fusion and fission.…”
Section: Mitochondrial Reshaping Is Required During T Cell Differenti...mentioning
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