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The voltage-gated potassium channel, Kv1.3, and the Ca -activated potassium channel, KCa3.1, regulate membrane potentials in T cells, thereby controlling T cell activation and cytokine production. However, little is known about the expression and function of potassium channels in human effector memory (EM) CD8 T cells that can be further divided into functionally distinct subsets based on the expression of the interleukin (IL)-7 receptor alpha (IL-7Rα) chain. Herein, we investigated the functional expression and roles of Kv1.3 and KCa3.1 in EM CD8 T cells that express high or low levels of the IL-7 receptor alpha chain (IL-7Rα and IL-7Rα , respectively). In contrast to the significant activity of Kv1.3 and KCa3.1 in IL-7Rα EM CD8 T cells, IL-7Rα EM CD8 T cells showed lower expression of Kv1.3 and insignificant expression of KCa3.1. Kv1.3 was involved in the modulation of cell proliferation and IL-2 production, whereas KCa3.1 affected the motility of EM CD8 T cells. The lower motility of IL-7Rα EM CD8 T cells was demonstrated using transendothelial migration and motility assays with intercellular adhesion molecule 1- and/or chemokine stromal cell-derived factor-1α-coated surfaces. Consistent with the lower migration property, IL-7Rα EM CD8 T cells were found less frequently in human skin. Stimulating IL-7Rα EM CD8 T cells with IL-2 or IL-15 increased their motility and recovery of KCa3.1 activity. Our findings demonstrate that Kv1.3 and KCa3.1 are differentially involved in the functions of EM CD8 T cells. The weak expression of potassium channels in IL-7Rα EM CD8 T cells can be revived by stimulation with IL-2 or IL-15, which restores the associated functions. This study suggests that IL-7Rα EM CD8 T cells with functional potassium channels may serve as a reservoir for effector CD8 T cells during peripheral inflammation.

Neurocognitive impairment (NCI) is one of the most relevant clinical manifestations of multiple sclerosis (MS). The profile of NCI and the structural and functional changes in the brain structures relevant for cognition in MS share some similarities to those in Alzheimer's disease (AD), the most common cause of neurocognitive disorders. Additionally, despite clear etiopathological differences between MS and AD, an accumulation of effector/memory CD8+ T cells and CD8+ tissue-resident memory T (Trm) cells in cognitively relevant brain structures of MS/AD patients, and higher frequency of effector/memory CD8+ T cells re-expressing CD45RA (TEMRA) with high capacity to secrete cytotoxic molecules and proinflammatory cytokines in their blood, were found. Thus, an active pathogenetic role of CD8+ T cells in the progression of MS and AD may be assumed. In this mini-review, findings supporting the putative role of CD8+ T cells in the pathogenesis of MS and AD are displayed, and putative mechanisms underlying their pathogenetic action are discussed. A special effort was made to identify the gaps in the current knowledge about the role of CD8+ T cells in the development of NCI to \"catalyze\" translational research leading to new feasible therapeutic interventions.

Acute infection with murine cytomegalovirus (mCMV) is controlled by CD8 + T cells and develops into a state of latent infection, referred to as latency, which is defined by lifelong maintenance of viral genomes but absence of infectious virus in latently infected cell types. Latency is associated with an increase in numbers of viral epitope-specific CD8 + T cells over time, a phenomenon known as “memory inflation” (MI). The “inflationary” subset of CD8 + T cells has been phenotyped as KLRG1 + CD62L - effector-memory T cells (iTEM). It is agreed upon that proliferation of iTEM requires repeated episodes of antigen presentation, which implies that antigen-encoding viral genes must be transcribed during latency. Evidence for this has been provided previously for the genes encoding the MI-driving antigenic peptides IE1-YPHFMPTNL and m164-AGPPRYSRI of mCMV in the H-2 d haplotype. There exist two competing hypotheses for explaining MI-driving viral transcription. The “reactivation hypothesis” proposes frequent events of productive virus reactivation from latency. Reactivation involves a coordinated gene expression cascade from immediate-early (IE) to early (E) and late phase (L) transcripts, eventually leading to assembly and release of infectious virus. In contrast, the “stochastic transcription hypothesis” proposes that viral genes become transiently de-silenced in latent viral genomes in a stochastic fashion, not following the canonical IE-E-L temporal cascade of reactivation. The reactivation hypothesis, however, is incompatible with the finding that productive virus reactivation is exceedingly rare in immunocompetent mice and observed only under conditions of compromised immunity. In addition, the reactivation hypothesis fails to explain why immune evasion genes, which are regularly expressed during reactivation in the same cells in which epitope-encoding genes are expressed, do not prevent antigen presentation and thus MI. Here we show that IE, E, and L genes are transcribed during latency, though stochastically, not following the IE-E-L temporal cascade. Importantly, transcripts that encode MI-driving antigenic peptides rarely coincide with those that encode immune evasion proteins. As immune evasion can operate only in cis , that is, in a cell that simultaneously expresses antigenic peptides, the stochastic transcription hypothesis explains why immune evasion is not operative in latently infected cells and, therefore, does not interfere with MI.

Specific pathogen‐free (SPF) laboratory mice have in recent years been criticized for their limited bench to bedside translational value, specifically within immunological and inflammatory research, due to their immature immune system caused by restricted pathogen exposure. Pathogenic reintroduction would result in the spread of infections, compromising staff safety and animal welfare and a risk of reducing reproducibility of in vivo studies. Previous studies have shown that preimmunizing SPF mice with inactivated murine pathogens efficiently induces increased levels of CD8+ effector memory T cells and higher inflammatory responses in a skin inflammation model. However, the method is laborious and carries infection risks if inactivation is improper. Therefore, a simpler and more standardized method is preferred to improve reproducibility and safety. We hypothesized that preimmunizing mice with an AP205 capsid virus‐like particle (cVLP) would be a safe, easy, and effective method to stimulate memory T cells in SPF mice and increase the inflammatory response in an ovalbumin‐induced (OVA) dermatitis model similar to the preimmunization with inactivated pathogens. The preimmunized mice seroconverted to the cVLP antigens, but the preimmunization did not induce higher levels of effector memory T cells compared to vehicle treated mice, nor did it affect the inflammatory response in the skin inflammation model. In conclusion, preimmunization with cVLP was not sufficient to induce a cellular immune response in the mice. Study Highlights What is the current knowledge on the topic? ○SPF mice have limited immunological memory due to restricted exposure to pathogenic stimuli, making their translational value for modeling certain human diseases questionable. What question did this study address? ○Can the adaptive immune response of SPF mice be preconditioned using a synthetic, noninfectious cVLP‐based immunization strategy to better mimic the immune status of adult humans and thereby increase their translational relevance? What does this study add to our knowledge? ○Preimmunization of SPF mice with two doses of a cVLP‐based vaccine is insufficient to activate enhanced memory T cell responses and did not impact the inflammatory response in an ovalbumin‐induced skin inflammation model. Activation of immunological memory is complex. How might this change clinical pharmacology or translational science? ○Stimulation of memory T cells is expected to create inflammatory mouse models that translate better to adult humans, but using this synthetic cVLP preimmunization is insufficient for this purpose.

Antigen-driven human effector-memory CD8+ T cells expressing low levels of the CD8β chain have been previously described. However, little is known on a possible antigen-independent trigger. We have examined the impact that IL-15 has on the expression of CD8β on purified human naïve CD8+ T cells after CFSE labeling and culture with IL-15. As expected, IL-15 induced naïve CD8+ T cells to proliferate and differentiate. Remarkably, the process was associated with a cell-cycle dependent down-modulation of CD8β from the cell surface, leading to the generation of CD8αβ low and CD8αβ − (i.e., CD8αα) T cells. In contrast, expression of the CD8α chain remained steady or even increased. Neither IL-2 nor IL-7 reproduced the effect of IL-15. Determination of mRNA levels for CD8α and CD8β isoforms by qPCR revealed that IL-15 promoted a significant decrease in mRNA levels of the CD8β M-4 isoform, while levels of the M-1/M-2 isoforms and of CD8α increased. Noteworthy, CD8+ T cell blasts obtained after culture of CD8+ T cells with IL-15 showed a cell-cycle dependent increase in the level of the tyrosine kinase Lck, when compared to CD8+ T cells at day 0. This study has shown for the first time that IL-15 generates CD8αα + αβ low and CD8αα + αβ − T cells containing high levels of Lck, suggesting that they may be endowed with unique functional features.

CD8 T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8 T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8 T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8 T cells are suppressed. In decidual CD8 T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8 T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8 T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8 T cells (CD8 EM cells) and naive CD8 T cells (CD8 N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8 T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8 T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCRβ repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8 EM cells was higher in the decidua than in the peripheral blood. CD8 EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8 EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8 EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8 EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8 EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.

Introduction and Objective This study explored the status of patients with chronic myeloid leukemia following the safe discontinuation of frontline or second‐line bosutinib treatment. The goal was to assess the long‐term outcomes and factors influencing treatment‐free remission (TFR) following cessation of bosutinib therapy. Methods The median duration of bosutinib treatment among 16 patients was 48 months. All patients achieved a deep molecular response before bosutinib discontinuation, which was sustained for a median pre‐cessation period of 27 months. Patients were monitored for molecular response and clinical outcomes. Results After bosutinib discontinuation, the major molecular response was lost in six patients: within 6 months in five patients and at 19 months in one patient. All six patients achieved a major molecular response after at least 3 months of bosutinib re‐treatment. Ten patients exhibited successful TFR without loss of major molecular response for a median duration of 48 (16–101) months. Kaplan–Meier analysis revealed a 68.8% treatment‐free survival at 12 months. After bosutinib cessation, eight patients developed Grade 1–2 withdrawal syndrome. No differences were observed in the clinical characteristics or bosutinib treatment between patients with TFR at 12 months (TFR group) and those without remission (recurrence group), except for the deep molecular response duration before bosutinib cessation (31 vs. 24 months, p = 0.009). T‐cell profiling using flow cytometry revealed a higher percentage of effector memory CD8+ T cells at 1 and 3 months after bosutinib discontinuation in the TFR group than in the recurrence group (p = 0.012 and p = 0.005, respectively). Conclusion Bosutinib can be safely discontinued under certain conditions, similar to other tyrosine kinase inhibitors. Additionally, T‐cell profile analysis before and after bosutinib discontinuation may predict successful TFR.

Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive ‘latent’ infection. This phenomenon, known as ‘memory inflation’ (MI), was found to be based on inflationary KLRG1+CD62L− effector-memory T cells (iTEM) that depend on repetitive restimulation. MI gained substantial interest for employing CMV as vaccine vector by replacing MI-driving CMV epitopes with foreign epitopes for generating high numbers of protective memory cells specific for unrelated pathogens. The concept of an MI-driving CMV vector is questioned by human studies disputing MI in humans. A bias towards MI in experimental models may have resulted from systemic infection. We have here studied local murine CMV infection as a route that is more closely matching routine human vaccine application. Notably, KLRG1−CD62L+ central memory T cells (TCM) and conventional KLRG1−CD62L− effector memory T cells (cTEM) were found to expand, associated with ‘avidity maturation’, whereas the pool size of iTEM steadily declined over time. The establishment of high avidity CD8 T-cell central memory encourages one to pursue the concept of CMV vector-based vaccines.

There is increasing evidence that in humans the adaptive immunological system can influence cognitive functions of the brain. We have undertaken a comprehensive immunological analysis of lymphocyte and monocyte populations as well as of HLA molecules expression in a cohort of elderly volunteers (age range, 64–101) differing in their cognitive status. Hereby, we report on the identification of a novel signature in cognitively impaired elderly characterized by: (1) elevated percentages of CD8+ T effector-memory cells expressing high levels of the CD45RA phosphate receptor (T emra hi ); (2) high percentages of CD8+ T cells expressing high levels of the CD8β chain (CD8β hi ); (3) augmented production of IFNγ by in vitro activated CD4+ T cells. Noteworthy, CD3+CD8+ T emra hi and CD3+CD8β hi cells were associated with impaired cognition. Cytomegalovirus seroprevalence showed that all volunteers studied but one were CMV positive. Finally, we show that some of these phenotypic and functional features are associated with an increased frequency of the HLA-B8 serotype, which belongs to the ancestral haplotype HLA-A1, Cw7, B8, DR3, DQ2, among cognitively impaired volunteers. To our knowledge, this is the first proof in humans linking the amount of cell surface CD45RA and CD8β chain expressed by CD8+ T emra cells, and the amount of IFNγ produced by in vitro activated CD4+ T cells, with impaired cognitive function in the elderly.

Murine models of cytomegalovirus (CMV) infection have revealed an immunological phenomenon known as “memory inflation” (MI). After a peak of a primary CD8+ T-cell response, the pool of epitope-specific cells contracts in parallel to the resolution of productive infection and the establishment of a latent infection, referred to as “latency.” CMV latency is associated with an increase in the number of cells specific for certain viral epitopes over time. The inflationary subset was identified as effector-memory T cells (iTEM) characterized by the cell surface phenotype KLRG1+CD127−CD62L−. As we have shown recently, latent viral genomes are not transcriptionally silent. Rather, viral genes are sporadically desilenced in a stochastic fashion. The current hypothesis proposes MI to be driven by presented viral antigenic peptides encoded by the corresponding, stochastically expressed viral genes. Although this mechanism suggests itself, independent evidence for antigen presentation during viral latency is pending. Here we fill this gap by showing that T cell-receptor transgenic OT-I cells that are specific for peptide SIINFEKL proliferate upon adoptive cell transfer in C57BL/6 recipients latently infected with murine CMV encoding SIINFEKL (mCMV-SIINFEKL), but not in those latently infected with mCMV-SIINFEKA, in which antigenicity is lost by mutation L8A of the C-terminal amino acid residue.