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Transient Early Blockade of the PD-1 Pathway Does Not Result in the Same Memory Defects as Permanent PD-1 Loss WT B6 mice were treated with anti-PD-1 antibody (clone 29F.1A12) or isotype control antibody (rat IgG2a) on days À1, 2, and 5 and harvested on day 8 p.i., or treated on days À1, 2, 5, and 8 and harvested on day 60 + p.i. PD-L1/L2 DKO mice were included as a control. (A and B) Representative plots (left) and summary (right) of KLRG1 and CD127 expression on D b GP 33-41 + CD8 + T cells in the lung at day 8 (A) or day 60 + (B) p.i. (C) Representative plots showing GP and CD44 staining in the lung on day 60 + p.i. Numbers on plots indicate the frequencies of D b GP 33-41 + cells of the CD8 + population (left). Summary of frequencies (of the CD8 + population, middle) and numbers (right) of D b GP 33-41 + T cells in the lung.
Source publication
The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8⁺ T cell memory following acute influenza infection, including reduced...
Contexts in source publication
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... circumvent these issues and to interrogate CD8 + T cell-intrinsic mechanisms of PD-1-mediated regulation, we cotransferred equal numbers of WT and PD-1 KO P14 TCR transgenic CD8 + T cells (recognizing the D b GP 33-41 epitope) into WT mice followed by infection with X31-GP33 virus. This approach did not alter viral load at day 8 p.i. compared with mice without P14 cells ( Figure S5A) and enabled direct comparison of WT and PD-1 KO CD8 + T cells in the same environment while controlling for precursor frequency, TCR repertoire, viral control, and influenza pathogenesis. Consistent with findings in germline KO mice, the frequency and numbers of PD-1 KO P14 cells were significantly higher than WT P14 cells in the lung and spleen at day 7 p.i. (Figure 3A), with similar trends in the blood and dLN (Fig- ure S5B). ...
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... approach did not alter viral load at day 8 p.i. compared with mice without P14 cells ( Figure S5A) and enabled direct comparison of WT and PD-1 KO CD8 + T cells in the same environment while controlling for precursor frequency, TCR repertoire, viral control, and influenza pathogenesis. Consistent with findings in germline KO mice, the frequency and numbers of PD-1 KO P14 cells were significantly higher than WT P14 cells in the lung and spleen at day 7 p.i. (Figure 3A), with similar trends in the blood and dLN (Fig- ure S5B). The higher frequency of PD-1 KO P14 cells during primary X31-GP33 virus infection was associated with increased bromodeoxyuridine (BrdU) incorporation in the spleen and dLN, but not the lung ( Figure 3B), indicating that PD-1 regulates CD8 + T cell proliferation in a cell-intrinsic manner in secondary lymphoid organs. ...
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... to global PD-1 pathway KO mice, PD-1 KO P14 cells in WT mice were more prone to cell death in the lung, as shown by increased FLICA staining at day 10 p.i. (Figure S5C). PD-1 KO P14 cells also underwent a more progressive contraction and were less abundant than WT P14 cells in the lung and spleen after 3 months ( Figure 3C; Figure S5D). ...
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... to global PD-1 pathway KO mice, PD-1 KO P14 cells in WT mice were more prone to cell death in the lung, as shown by increased FLICA staining at day 10 p.i. (Figure S5C). PD-1 KO P14 cells also underwent a more progressive contraction and were less abundant than WT P14 cells in the lung and spleen after 3 months ( Figure 3C; Figure S5D). Moreover, PD-1 KO memory P14 cells showed significantly reduced interferon gamma (IFNg) and tumor necrosis factor alpha (TNF-a) coproduction and a decreased amount of IFNg made per cell compared with Figure 3D; Figure S5E). ...
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... KO P14 cells also underwent a more progressive contraction and were less abundant than WT P14 cells in the lung and spleen after 3 months ( Figure 3C; Figure S5D). Moreover, PD-1 KO memory P14 cells showed significantly reduced interferon gamma (IFNg) and tumor necrosis factor alpha (TNF-a) coproduction and a decreased amount of IFNg made per cell compared with Figure 3D; Figure S5E). Hence, although the kinetics differed, these results were consistent with the quantitative and qualitative memory attrition observed in the global KO mice. ...
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... administered anti-PD-1 blocking antibody to WT B6 mice early during X31-GP33 infection (day À1 through 8), and compared effector (day 8 p.i.) and memory (day 60 + p.i.) responses to isotype control (Rat Immunoglobulin (Ig)G2a)-treated WT B6 mice or PD-L1/L2 DKO mice as controls. Figure 5A), suggesting that blockade of PD-1 had effects similar to genetic PD-1 pathway deficiency during the effector phase. These phenotypic differences were not sustained at the memory time point (Fig- ure 5B). ...
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... 5A), suggesting that blockade of PD-1 had effects similar to genetic PD-1 pathway deficiency during the effector phase. These phenotypic differences were not sustained at the memory time point (Fig- ure 5B). There were no differences in CD127 + KLRG1 À ( Figures 5A and 5B) D b GP 33-41 + CD8 + T cells at either time point. ...
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... phenotypic differences were not sustained at the memory time point (Fig- ure 5B). There were no differences in CD127 + KLRG1 À ( Figures 5A and 5B) D b GP 33-41 + CD8 + T cells at either time point. At day 60 + , there was a quantitative defect in memory observed in PD-L1/L2 DKO that was not seen in anti-PD-1-treated mice (Fig- ure 5C). ...
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... were no differences in CD127 + KLRG1 À ( Figures 5A and 5B) D b GP 33-41 + CD8 + T cells at either time point. At day 60 + , there was a quantitative defect in memory observed in PD-L1/L2 DKO that was not seen in anti-PD-1-treated mice (Fig- ure 5C). Collectively, these data suggest that restricting PD-1 pathway deficiency to the priming stage of influenza led to similar phenotypic changes during the effector phase but did not result in the same memory defect observed in the absence of PD-1 signals. ...
Citations
... However, the role of CXCR5 + CD8+ in B cell activation is more speculative 40 . CXCR5 + CD8 + T cells that co-express PD-1+ and the transcription factor, Tcf1, have been shown to be induced in response to chronic viral infections and tumors and expansion after treatment with PD-1 blockers is associated with clearance 39,41 . This is the first report of an Data that did not pass the normality test was first logarithmically transformed to conform to normality and then tested for significance. ...
Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants’ second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.
... Correspondingly, the fraction of cells in the effector memory (EM) population (CD62L−, CD44+) was lower in 6 m primed mice compared to 9 m primed mice. We also measured the expression of PD-1 as this inhibitory marker has been suggested to play a role in memory formation and to restrain the early expansion of virus-specific CD8+ T cells during acute respiratory infections [32]. The percentage of PD-1+ T cells within the ASN-specific T-cell population of 9 m primed mice was significantly higher than in 6 m primed mice (Supplementary Figure S2D,E). ...
To protect older adults against influenza A virus (IAV) infection, innovative strategies are imperative to overcome the decrease in protective immune response with age. One approach involves the boosting of CD8+ T cells at middle age that were previously induced by natural infection. At this stage, the immune system is still fit. Given the high conservation of T-cell epitopes within internal viral proteins, such a response may confer lasting protection against evolving influenza strains at older age, also reducing the high number of influenza immunizations currently required. However, at the time of vaccination, some individuals may have been more recently exposed to IAV than others, which could affect the T-cell response. We therefore investigated the fundamental principle of how the interval between the last infection and booster immunization during middle age influences the CD8+ T-cell response. To model this, female mice were infected at either 6 or 9 months of age and subsequently received a heterosubtypic infection booster at middle age (12 months). Before the booster infection, 6-month-primed mice displayed lower IAV-specific CD8+ T-cell responses in the spleen and lung than 9-month-primed mice. Both groups were better protected against the subsequent heterosubtypic booster infection compared to naïve mice. Notably, despite the different CD8+ T-cell levels between the 6-month- and 9-month-primed mice, we observed comparable responses after booster infection, based on IFNγ responses, and IAV-specific T-cell frequencies and repertoire diversity. Lung-derived CD8+ T cells of 6- and 9-month-primed mice expressed similar levels of tissue-resident memory-T-cell markers 30 days post booster infection. These data suggest that the IAV-specific CD8+ T-cell response after boosting is not influenced by the time post priming.
... Anti-PD-1/PD-L1 therapy is an effective treatment for patients with metastatic NSCLC lacking sensitizing EGFR or ALK mutations (9)(10)(11)(12)(13). The primary anticancer mechanism of anti-PD-L1 or anti-PD-1 antibody is thought to prevent PD-1 antitumor T cells from being inhibited by cell surface-expressed PD-L1, leading to T-cell resuscitation (14), reduced T-cell depletion or death, and increased T-cell memory and intratumoral antitumor immune cell infiltration (15)(16)(17)(18)(19). PD-L1 expressed on tumor cells is considered to be a biomarker for predicting immune checkpoint inhibitors (ICIs) efficacy in patients with NSCLC (20). ...
Non–small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers. In recent years, treatment with immune checkpoint inhibitors (ICIs) has gradually improved the survival rate of patients with NSCLC, especially those in the advanced stages. ICIs can block the tolerance pathways that are overexpressed by tumor cells and maintain the protective activity of immune system components against cancer cells. Emerging clinical evidence suggests that gut microbiota may modulate responses to ICIs treatment, possibly holding a key role in tumor immune surveillance and the efficacy of ICIs. Studies have also shown that diet can influence the abundance of gut microbiota in humans, therefore, dietary interventions and the adjustment of the gut microbiota is a novel and promising treatment strategy for adjunctive cancer therapy. This review comprehensively summarizes the effects of gut microbiota, antibiotics (ATBs), and dietary intervention on the efficacy of immunotherapy in NSCLC, with the aim of informing the development of novel strategies in NSCLC immunotherapy.
... However, this contradicted CD8 + T cell characteristics in RCC [10,11,15]. Recent studies have reported that the timing of PD-1 inhibition could negatively affect T-cell priming and memory CD8 + T cell formation, thus contributing to more appropriate timings in RCC immunotherapy [16,17]. ...
Background
Kidney cancer is an immunogenic solid tumor, characterized by high tumor burden and infiltration of CD8⁺ T cells. Although immunotherapy targeting the PD1/CTLA-4 axis has demonstrated excellent clinical efficacy, clinical outcomes in most patients are poor.
Methods
We used the RNA sequencing data from the GEO database for KIRC GSE121636 and normal kidney tissue GSE131685, and performed single-cell analysis for cluster identification, pathway enrichment, and CD8⁺ T cell-associated gene identification. Subsequently, the significance of different CD8⁺ T-cell associated gene subtypes was elucidated by consensus clustering, pathway analysis, mutated gene analysis, and KIRC immune microenvironment analysis in the TCGA–KIRC disease cohort. Single gene analysis identified LAG3 as the most critical CD8⁺ T-cell-associated gene and its function was verified by cell phenotype and immunohistochemistry in KIRC.
Results
In the present study, CD8⁺ T-cell associated genes in KIRC were screened, including GZMK, CD27, CCL4L2, FXYD2, LAG3, RGS1, CST7, DUSP4, CD8A, and TRBV20-1 and an immunological risk prognostic model was constructed (risk score = − 0.291858656434841*GZMK − 0.192758342489394*FXYD2 + 0.625023643446193*LAG3 + 0.161324477181591*RGS1 − 0.380169045328895*DUSP4 − 0.107221347575037*TRBV20-1). LAG3 was identified and proved as the most critical CD8⁺ T cell-associated gene in KIRC.
Conclusion
We proposed and constructed an immunological risk prognostic model for CD8⁺ T cell-associated genes and identified LAG3 as a pivotal gene for KIRC progression and CD8⁺ T-cell infiltration. The model comprehensively explained the immune microenvironment and provided novel immune-related therapeutic targets and biomarkers in KIRC.
... In addition, abrogating PD-1 signaling during influenza virus infection improved viral clearance and increased CD8 1 T cell production of IFN-g and granzyme B (27). PD-1 signaling has been implicated in optimal CD8 1 memory T cell formation following influenza infection, suggesting that the timing of PD-1 blockade during acute viral infection is important to enhance CD8 1 T cell function while not impairing memory formation (28). However, the effects of PD-1 blockade on the aged CD8 1 T cell response and T RM cell formation during HMPV infection are poorly understood. ...
... The significant increase in engraftment of Pdcd1 À/À lymphocytes was also observed in a prior mixed BM chimera model (15). Others have found that the absence of PD-1 can cause an increase in activation and proliferation of T lymphocytes (28,39), which could provide one explanation for this finding. We report the absolute cell numbers for these transplant results to try to account for the differences in engraftment. ...
... This CD8 1 T RM accumulation was impaired in aged Pdcd1 À/À mice, which leads to the hypothesis that PD-1 signaling may be impacting the formation and accumulation of this CD8 1 memory T cell population in the aged host. PD-1 signaling is required for optimal CD8 1 memory T cell formation (28,50). These studies reported that the timing of PD-1 blockade was important to optimize effector CD8 1 T cell function without severely limiting memory formation (28,41). ...
CD8+ T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8+ T cells are the primary cell type responsible for viral clearance. With increasing age, CD8+ T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (TRM) CD8+ T cells. We sought to elucidate the role of PD-1 signaling on aged CD8+ T cell function and accumulation of CD8+ TRM cells during acute viral respiratory tract infection, given the importance of PD-1 regulating CD8+ T cells during acute and chronic infections. PD-1 blockade or genetic ablation in aged mice yielded improved CD8+ T cell granzyme B production comparable to that in young mice during human metapneumovirus and influenza viral infections. Syngeneic transplant and adoptive transfer strategies revealed that improved granzyme B production in aged Pdcd1−/− CD8+ T cells was primarily cell intrinsic because aged wild-type CD8+ T cells did not have increased granzyme B production when transplanted into a young host. PD-1 signaling promoted accumulation of cytotoxic CD8+ TRM cells in aged mice. PD-1 blockade of aged mice during rechallenge infection resulted in improved clinical outcomes that paralleled reduced accumulation of CD8+ TRM cells. These findings suggest that PD-1 signaling impaired CD8+ T cell granzyme B production and contributed to CD8+ TRM cell accumulation in the aged lung. These findings have implications for future research investigating PD-1 checkpoint inhibitors as a potential therapeutic option for elderly patients with severe respiratory viral infections.
... Data are represented as mean G SD. See also Figures S1 and S2. 47 These elevations in immunomodulatory markers resolved and were not significant between groups at Month 3 or Year 1 ( Figure S3). To investigate functional differences contributing to the divergence in the clinical course, we identified marker/cell type combinations that were significantly different between symptomatic and asymptomatic participants. ...
... Data from all the assay platforms were integrated using a joint dimension reduction with multi-omics factor analysis (MOFA2) to construct multiomics modules. 78,79 MOFA factors were derived to explain variabilities across samples for CyTOF (34 cell type proportions), per-cell type functional marker expression levels (580 combinations), proteomics (265 proteins), metabolomics (578 metabolites), Seq-Well cell-type-specific average gene expression levels (7610) and average cell-type-specific module expression levels from Seq-Well (47). The omics data were aligned for the 28 available samples. ...
Infection with West Nile virus (WNV) drives a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence employing single-cell protein and transcriptional profiling complemented with matched serum proteomics and metabolomics as well as multi-omics analysis. At the acute time point, we detected both elevation of pro-inflammatory markers in innate immune cell types and reduction of regulatory T cell activity in participants with severe infection, whereas asymptomatic donors had higher expression of genes associated with anti-inflammatory CD16⁺ monocytes. Therefore, we demonstrated the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.
... Interestingly, not only did we observe enrichment for HLA-E:NKG2A, which suggests that there may be active engagement of NKG2A in tumors, but we also observed increased chemokine, cytokine, and exhaustion receptor engagement. This suggests active recruitment of immune cells, consistent with increased immune in ltration in bulk RNA-seq samples, and suggests the possibility of tumor-immune cell engagement, for example through the well-known PD-1:PD-L1 axis [74][75][76] . Thus, we demonstrate across dozens of cancer types, thousands of patients, and hundreds of thousands of tumorin ltrating CD8 + T cells, that NKG2A + biases associate with increased survival and immune in ltration of tumors, as con rmed through in situ measurements, possibly due to the acquirement of a T RM phenotype by NKG2A + CD8 + T cells that allows for sustained anti-tumor effector T cell responses. ...
Infection, autoimmunity, and cancer are the principal human health challenges of the 21st century and major contributors to human death and disease. Often regarded as distinct ends of the immunological spectrum, recent studies have hinted there may be more overlap between these diseases than appears. For example, pathogenic inflammation has been demonstrated as conserved between infection and autoimmune settings. T resident memory (T RM ) cells have been highlighted as beneficial for infection and cancer. However, these findings are limited by patient number and disease scope; exact immunological factors shared across disease remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A ⁺ immune bias as associative with protection against disease severity, mortality, and autoimmune and post-acute chronic disease. We reveal that NKG2A ⁺ CD8 ⁺ T cells correlate with reduced inflammation, increased humoral immunity, and resemble T RM cells. Our results suggest that an NKG2A ⁺ bias is a pan-disease immunological factor of protection and thus supports recent suggestions that there is immunological overlap between infection, autoimmunity, and cancer. Our findings underscore the promotion of an NKG2A ⁺ biased response as a putative therapeutic strategy.
... 4,17 Antigen, costimulatory, and inhibitory receptors of T cells have all been implicated in the cell fate decision to differentiate or self-renew. [18][19][20][21] Those same receptors can also undergo dynamic subcellular repositioning in activated and dividing T cells. [22][23][24] We therefore examined the localization of key signaling molecules in mitotic T cells as well as the incipient cell fate of daughter T cells responding to tumor challenge and in the context of therapeutic PD-1 blockade. ...
... Insofar as PD-1 may play a causal role in maintaining self-renewal of TCF1 + T cells, [18][19][20][21] we took a candidate approach of examining the positioning of CD73, an ectonucleotidase that may also mark and maintain self-renewing T cells. 27 As observed for polarity of PD-1, the polarity of CD73 in interphase LN T cell blasts is frequently localized opposite the activating hub ( Figures 2D and 2E). ...
... This finding may be consistent with the proposition that loss of inhibitory signals lowers the threshold for activating T cells and silencing TCF1. [18][19][20][21]29 Results similar to the confocal analyses were obtained using CMT167 challenge and imaging cytometry. We readily detected sibling cell pairs with discordant expression of TCF1 and some sibling cell pairs with concordant expression of TCF1 in all treatment arms ( Figures S3A-S3C). ...
The ability of activated progenitor T cells to self-renew while producing differentiated effector cell descendants may underlie immunological memory and persistent responses to ongoing infection. The nature of stem-like T cells responding to cancer and during treatment with immunotherapy is not clear. The subcellular organization of dividing progenitor CD8⁺ T cells from mice challenged with syngeneic tumors is examined here. Three-dimensional microscopy reveals an activating hub composed of polarized CD3, CD28, and phosphatidylinositol 3-kinase (PI3K) activity at the putative immunological synapse with an inhibitory hub composed of polarized PD-1 and CD73 at the opposite pole of mitotic blasts. Progenitor T cells from untreated and inhibitory checkpoint blockade-treated mice yield a differentiated TCF1⁻ daughter cell, which inherits the PI3K activation hub, alongside a discordantly fated, self-renewing TCF1⁺ sister cell. Dynamic organization of opposite activating and inhibitory signaling poles in mitotic lymphocytes may account for the enigmatic durability of specific immunity.
... However, the effects of prolonged blockade on overall T cell responses on nominal antigens or with recall responses have not been well characterized in both mouse studies and clinical assessment. Evidence using PD-1 -/mice suggests that impairment of memory T cell responses or maintenance occurs with loss of PD-1 (32,33), resulting in worsening "exhaustion" and reduced survival months after chronic viral infection (33). The mechanism underlying the impaired function in the mice was unclear but is consistent with our results of increased AICD and T cell loss during states of high stimulation as possibly contributing. ...
Bystander activation of memory T cells occurs via cytokine signaling alone in the absence of T cell receptor (TCR) signaling and provides a means of amplifying T cell effector responses in an antigen-nonspecific manner. While the role of Programmed Cell Death Protein 1 (PD-1) on antigen-specific T cell responses is extensively characterized, its role in bystander T cell responses is less clear. We examined the role of the PD-1 pathway during human and mouse non–antigen-specific memory T cell bystander activation and observed that PD-1⁺ T cells demonstrated less activation and proliferation than activated PD-1– populations in vitro. Higher activation and proliferative responses were also observed in the PD-1– memory population in both mice and patients with cancer receiving high-dose IL-2, mirroring the in vitro phenotypes. This inhibitory effect of PD-1 could be reversed by PD-1 blockade in vivo or observed using memory T cells from PD-1–/– mice. Interestingly, increased activation through abrogation of PD-1 signaling in bystander-activated T cells also resulted in increased apoptosis due to activation-induced cell death (AICD) and eventual T cell loss in vivo. These results demonstrate that the PD-1/PD-Ligand 1 (PD-L1) pathway inhibited bystander-activated memory T cell responses but also protected cells from AICD.
... As discussed above, exhausted CD8 + T cells express multiple IRs at persistent levels, and ligands related to these IRs are upregulated on antigen-presenting cells (APCs), tumor cells, and nonimmune cells during chronic infections and in cancer. Notably, PD-1 is transiently upregulated during T-cell activation and is required for memory formation [83]. In the contexts of chronic infections and cancer, the expression of PD-1 is maintained at high levels on exhausted cells, which suppresses their effector function. ...
... The following hypotheses may be tested. First, PD-1 expression is crucial for T-cell exhaustion, but several studies have indicated that in the acute infection context, PD-1 expression is required for optimal memory T-cell development [83,225]. Thus, the Foxo1-PD-1 axis might be important for both exhausted and memory T-cell formation. ...
CD8 ⁺ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8 ⁺ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8 ⁺ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8 ⁺ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8 ⁺ T cells at the molecular level.
