Bimodal Effect of NKG2A Blockade on Intratumoral and Systemic CD8 T Cell Response Induced by Cancer Vaccine.

Immune check-point blockade (ICB) has revitalized cancer immunotherapy, showing unprecedented efficacy despite only a narrow number of indications and with limited long-term protection. Cancer vaccines are promising combination partners for ICB to widen the patient population profiting from these treatments. Therapeutic heterologous prime-boost vaccination with KISIMATM protein vaccine and VSV-GP-TAg oncolytic virus was shown to inflame the tumor microenvironment, promoting significant infiltration of antigen-specific CD8 T cells resulting in robust antitumoral efficacy in mouse tumor models, and clinical trials are currently ongoing. Here, we report the impact of NKG2A blockade on antitumoral CD8 T cell immune response elicited by KISIMA-VSV-GP-TAg vaccination in tumor mouse models. Combination therapy significantly reduced the amount of vaccine-induced exhausted CD8 T cells infiltrating the tumor, resulting in short-term improved tumor growth control and prolonged mouse survival, while it also influenced the establishment of systemic effector memory CD8 T cell response. Taken together, these data show a compartment-dependent effect of NKG2A blockade on cancer vaccine-induced T cell immunity, increasing intratumoral T cell efficacy and attenuating the development of peripheral effector memory CD8 T cell response.

Bone marrow CD8+ Trm cells induced by IL-15 and CD16+ monocytes contribute to HSPC destruction in human severe aplastic anemia.

Idiopathic severe aplastic anemia (SAA) is a disease of bone marrow failure caused by T-cell-induced destruction of hematopoietic stem and progenitor cells (HSPCs), however the mechanism remains unclear. We performed single-cell RNA sequencing of PBMCs and BMMCs from SAA patients and healthy donors and identified a CD8+ T cell subset with a tissue residency phenotype (Trm) in bone marrow that exhibit high IFN-γ and FasL expression and have a higher ability to induce apoptosis in HSPCs in vitro through FasL expression. CD8+ Trm cells were induced by IL-15 presented by IL-15Rα on monocytes, especially CD16+ monocytes, which were increased in SAA patients. CD16+ monocytes contributed to IL-15-induced CD38+CXCR6+ pre-Trm differentiation into CD8+ Trm cells, which can be inhibited by the CD38 inhibitor 78c. Our results demonstrate that IL-15-induced CD8+ Trm cells are pathogenic cells that mediate HSPC destruction in SAA patients and are therapeutic targets for future treatments.

TCR-signals downstream adversely correlate with the survival signals of memory CD8+ T cells under homeostasis.

The significance of self-peptide-MHC-I/TCR (SMT) interaction in the survival of CD8+ T cells during naïve- and developmental-stages is well documented. However, the same for the memory stage is contentious. Previous studies have attempted to address the issue using MHC-I or TCR deficient systems, but inconsistent findings with memory CD8+ T cells of different TCR specificities have complicated the interpretation. Differential presence and/or processing of TCR-signals downstream in memory CD8+ T cells of different TCR specificities could be thought of as a reason. In this study, we examined the TCR-signals downstream in memory CD8+ T cells and compared them to the presence of survival-related signals (Annexin-V, Bcl-2, and Ki-67). We categorically tracked foreign antigen-experienced memory CD8+ T (TM) cells generated after Plasmodium pre-erythrocytic-stage malaria infection in C57BL/6 mice. Interestingly, we found that memory CD8+ T cells had more TCR-signals downstream than naive cells. We reasoned and attributed the increased expression of cell adhesion molecules to the enhanced TCR-signaling. TCR-signals downstream correlate more closely with survival signals in naive CD8+ T cells than with death signals in TM cells. Further investigation using antigen-specific CD8+ T cells and diverse infection systems would aid in conceptualizing the findings.

GOT1 regulates CD8+ effector and memory T cell generation.

T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.

Antigen-presenting B cells promote TCF-1+ PD1- stem-like CD8+ T-cell proliferation in glioblastoma.

Understanding the spatial relationship and functional interaction of immune cells in glioblastoma (GBM) is critical for developing new therapeutics that overcome the highly immunosuppressive tumor microenvironment. Our study showed that B and T cells form clusters within the GBM microenvironment within a 15-µm radius, suggesting that B and T cells could form immune synapses within the GBM. However, GBM-infiltrating B cells suppress the activation of CD8+ T cells. To overcome this immunosuppression, we leveraged B-cell functions by activating them with CD40 agonism, IFNγ, and BAFF to generate a potent antigen-presenting B cells named BVax. BVax had improved antigen cross-presentation potential compared to naïve B cells and were primed to use the IL15-IL15Ra mechanism to enhance T cell activation. Compared to naïve B cells, BVax could improve CD8 T cell activation and proliferation. Compared to dendritic cells (DCs), which are the current gold standard professional antigen-presenting cell, BVax promoted highly proliferative T cells in-vitro that had a stem-like memory T cell phenotype characterized by CD62L+CD44- expression, high TCF-1 expression, and low PD-1 and granzyme B expression. Adoptive transfer of BVax-activated CD8+ T cells into tumor-bearing brains led to T cell reactivation with higher TCF-1 expression and elevated granzyme B production compared to DC-activated CD8+ T cells. Adoptive transfer of BVax into an irradiated immunocompetent tumor-bearing host promoted more CD8+ T cell proliferation than adoptive transfer of DCs. Moreover, highly proliferative CD8+ T cells in the BVax group had less PD-1 expression than those highly proliferative CD8+ T cells in the DC group. The findings of this study suggest that BVax and DC could generate distinctive CD8+ T cells, which potentially serve multiple purposes in cellular vaccine development.

Alveolar macrophages instruct CD8+ T cell expansion by antigen cross-presentation in lung.

Lung CD8+ memory T cells play central roles in protective immunity to respiratory viruses, such as influenza A virus (IAV). Here, we find that alveolar macrophages (AMs) function as antigen-presenting cells that support the expansion of lung CD8+ memory T cells. Intranasal antigen administration to mice subcutaneously immunized with antigen results in a rapid expansion of antigen-specific CD8+ T cells in the lung, which is dependent on antigen cross-presentation by AMs. AMs highly express interleukin-18 (IL-18), which mediates subsequent formation of CD103+CD8+ resident memory T (TRM) cells in the lung. In a mouse model of IAV infection, AMs are required for expansion of virus-specific CD8+ T cells and CD103+CD8+ TRM cells and inhibiting virus replication in the lungs during secondary infection. These results suggest that AMs instruct a rapid expansion of antigen-specific CD8+ T cells in lung, which protect the host from respiratory virus infection.

Keeping T cell memories in mind.

The mammalian central nervous system (CNS) contains a vibrant community of resident adaptive immune cells at homeostasis. Among these are memory CD8+ and CD4+ T cells, which reside in the CNS in the settings of health, aging, and neurological disease. These T cells commonly exhibit a tissue-resident memory (TRM) phenotype, suggesting that they are antigen-experienced and remain separate from the circulation. Despite these characterizations, T cell surveillance of the CNS has only recently been studied through the lens of TRM immunology. In this Review, we outline emerging concepts of CNS TRM generation, localization, maintenance, function, and specificity. In this way, we hope to highlight roles of CNS TRM in health and disease to inform future studies of adaptive neuroimmunity.

[Competition between T Cells for a Finite Epidermal Niche Promotes Selective Retention of Antigen-specific Memory T Cells in the Epidermis].

Tissue-resident memory T cells are a highly abundant, non-blood circulating subset of memory T cells. These appear to be the most protective population of memory T cells at barrier surfaces. Long-term retention and survival of tissue-resident memory CD8+ T cells (Trm) is determined by tissue-derived signals, such as keratinocyte-mediated activation of transforming growth factor ß (TGFß) in the epidermis. We found that T cell clones compete for limited amounts of active TGFß and pre-existing Trm could be replaced with newly recruited effector T cells in the epidermis. On the other hand, when effector T cells transition into Trm, the presence of cutaneous cognate antigen increases the fitness of individual Trm clones in the epidermal niche. Thus, antigen-specific Trm are more efficiently retained than bystander Trm that have not encountered cognate antigens when they compete with newly recruited effector T cells for limited active TGFß. Therefore, competition between T cells for active TGFß represents a selective pressure that promotes the accumulation of antigen-specific Trm cells in the epidermal niche. Furthermore, our model implies that the epidermis offers a finite niche for maintaining Trm. Although the epidermal niche of Trm cannot represent the capacity of T cell-mediated immune memory in our body, these findings might suggest a challenge for the accommodation of memory T cells specific to multiple pathogens throughout a lifetime.

mTOR participates in the formation, maintenance, and function of memory CD8+T cells regulated by glycometabolism.

Memory CD8+T cells participate in the fight against infection and tumorigenesis as well as in autoimmune disease progression because of their efficient and rapid immune response, long-term survival, and continuous differentiation. At each stage of their formation, maintenance, and function, the cell metabolism must be adjusted to match the functional requirements of the specific stage. Notably, enhanced glycolytic metabolism can generate sufficient levels of adenosine triphosphate (ATP) to form memory CD8+T cells, countering the view that glycolysis prevents the formation of memory CD8+T cells. This review focuses on how glycometabolism regulates memory CD8+T cells and highlights the key mechanisms through which the mammalian target of rapamycin (mTOR) signaling pathway affects memory CD8+T cell formation, maintenance, and function by regulating glycometabolism. In addition, different subpopulations of memory CD8+T cells exhibit different metabolic flexibility during their formation, survival, and functional stages, during which the energy metabolism may be critical. These findings which may explain why enhanced glycolytic metabolism can give rise to memory CD8+T cells. Modulating the metabolism of memory CD8+T cells to influence specific cell fates may be useful for disease treatment.

Prognostic Impact of Memory CD8(+) T Cells on Immunotherapy in Human Cancers: A Systematic Review and Meta-Analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to determine the prognostic value of memory CD8(+) T cells in cancer patients with immunotherapy. METHODS: EMBASE, MEDLINE (PubMed), and Web of Science databases were searched to identify suitabile articles published before March 2021. Risk of bias on the study level was assessed using the Cochrane Bias Risk Assessment Tool. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled progression-free survival (PFS) and overall survival (OS) were calculated using RevMan 5.4 to evaluate the prognostic impact of memory CD8(+) T cells. RESULTS: In total, nine studies were included in the final analysis. High levels of memory CD8(+) T cells were significantly closely correlated with better progression-free survival (PFS) and overall survival (OS) of cancer patients with immunotherapy (PFS, HR 0.64, 95% CI 0.53-0.78; OS, HR 0.37, 95% CI 0.21-0.65). Memory CD8(+) T cells still have significant prognostic value in cancer patients given immunotherapy alone after excluding of other interfering factors such as chemotherapy, radiotherapy, and targeted therapy (PFS, HR 0.65, 95% CI 0.48-0.89; OS, HR 0.23, 95% CI 0.13-0.42). However, high memory CD8(+) T cells levels did not correspond to a longer PFS or OS in cancer patients with non-immunotherapy (PFS, HR 1.05, 95% CI 0.63-1.73; OS, HR 1.29, 95% CI 0.48-3.48). Thus, memory CD8(+) T cells might be a promising predictor in cancer patients with immunotherapy. CONCLUSIONS: The host's overall immune status, and not only the tumor itself, should be considered to predict the efficacy of immunotherapy in cancer patients. This study is the first to show the significant prognostic value of memory CD8(+) T cells in immunotherapy of cancer patients through systematic review and meta-analysis. Thus, the detection of memory CD8(+) T cells has a considerable value in clinical practice in cancer patients with immunotherapy. Memory CD8(+) T cells may be promising immunotherapy targets.

Enhanced immune memory through a constant photothermal-metabolism regulation for cancer prevention and treatment.

Tumor vaccine inducing effective and perdurable antitumor immunity has a great potential for cancer prevention and therapy. The key indicator for a successful tumor vaccine is boosting the immune system to produce more memory T cells. Although many tumor vaccines have been designed, few of them involve in actively regulating immune memory CD8+T cells. Here a tumor vaccine vector (TA-Met@MS) by encapsulating tumor antigen (TA), metformin (Met) and Hollow gold nanospheres (HAuNS) into poly (lactic-co-glycolic acid) (PLGA) microspheres was presented. TA via the treatment of photothermal therapy (PTT) showed high immunogenicity and immune-adjuvant effectiveness. And NIR light-mediated photothermal effect can lead to a pulsed-release behavior of TA and Met from the microspheres. The released TA can regulate primary T cell expansion and contraction, and stimulate the production of effector T cells at the early immunization stage. The metabolic behavior of the cells is then intervened from glycolysis into fatty acids oxidation (FAO) through the activation of AMPK mediated by Met, which can enhance T cell survival and facilitate the differentiation of memory CD8+T cells. This study may present a valuable insight to design tumor vaccine for enhanced cancer prevention and therapy.

Bacterial Infection with Listeria monocytogenes in Mice and Subsequent Analysis of Antigen-Specific CD8 T Cell Responses.

Pathogens such as bacteria, viruses, fungi, or protozoa can cause acute and chronic infections in their hosts. The intracellular bacterium Listeria monocytogenes serves as a model pathogen to assess the molecular mechanisms regulating CD8 T cell activation, differentiation, and function. We set up an experimental workflow to investigate cell-intrinsic roles of the nuclear receptor NR2F6 in CD8 T cell memory formation upon Listeria monocytogenes (LmOVA) infection ( Jakic et al., 2021 ). The current protocol details how to cultivate ovalbumin-expressing LmOVA, infect naïve C57BL/6 mice with these bacteria and determine the bacterial load in host organs. Furthermore, we describe how to evaluate antigen-specific CD8 T cell responses and discriminate between short-lived effector and memory precursor cells in vivo following LmOVA infection (Figure 1). To assess CD8 T cell-intrinsic molecular mechanisms, we integrated an adoptive cell transfer (ACT) experiment of genetically modified naïve OT-I CD8 T cells into congenic hosts before LmOVA infection. Graphic abstract: Figure 1.Experimental workflow depicting the steps for infection of mice with Listeria and subsequent analysis of antigen-specific CD8 memory responses. Bacteria (ovalbumin expressing Listeria monocytogenes) are thawed and grown on lysogeny broth (LB) plates overnight (ON). A single colony is picked and grown in LB medium ON. Bacteria from the exponential growth phase are then injected into a C57BL/6 mouse via tail vein injection. Colony forming units (CFU) of the bacteria can be detected in the spleen on day 3 post injection. Antigen-specific CD8 T cell immune response can be investigated during the acute phase (d3 after infection), during the peak of the adaptive immune response (d7), the clearance phase (d26), or the memory phase (d70) by flow cytometry. Created with BioRender.com.

The role of CD8 T cells in controlling HIV beyond the antigen-specific face.

OBJECTIVES: Understanding the determinants of HIV immune control is important for seeking viable HIV prevention, treatment and curative strategies. The antigen-specific roles of CD8 T cells in controlling primary HIV infection have been well documented, but their abilities to control the latent HIV reservoir is less well studied. METHODS: The scientific literature on this issue was searched on PubMed. RESULTS: Recent reports have demonstrated that CD8 T cells are also involved in the control of viral replication in HIV-infected individuals receiving antiretroviral therapy (ART). However, based on accumulating evidence, the antiviral role of CD8 T cells in ART patients may not be achieved via an antigen-specific manner as HIV-specific CD8 T cells can sense, but not effectively eliminate, cells harbouring intact provirus without first being activated. Our recent study indicated that virtual memory CD8 T cells, a semi-differentiated component of CD8 T cells, may be involved in the mechanism restraining the HIV DNA reservoir in ART patients. CONCLUSIONS: In this review, we summarize recent findings on the role of CD8 T cells in controlling HIV, highlighting differences between conventional antigen-specific and innate-like CD8 T cells. A better understanding of the roles of CD8 T cells during HIV infection should benefit the informed design of immune-based treatment strategies.

Persistent lentivirus infection induces early myeloid suppressor cells expansion to subvert protective memory CD8 T cell response✰,✰✰.

BACKGROUND: Memory CD8+T cell responses play an essential role in protection against persistent infection. However, HIV-1 evades vaccine-induced memory CD8+T cell response by mechanisms that are not fully understood. METHODS: We analyzed the temporal dynamics of CD8+T cell recall activity and function during EcoHIV infection in a potent PD1-based vaccine immunized immunocompetent mice. FINDINGS: Upon intraperitoneal EcoHIV infection, high levels of HIV-1 GAG-specific CD8+T lymphocytes recall response reduced EcoHIV-infected cells significantly. However, this protective effect diminished quickly after seven days, followed by a rapid reduction of GAG-specific CD8+T cell number and activity, and viral persistence. Mechanistically, EcoHIV activated dendritic cells (DCs) and myeloid cells. Myeloid cells were infected and rapidly expanded, exhibiting elevated PD-L1/-L2 expression and T cell suppressive function before day 7, and were resistant to CD8+T cell-mediated apoptosis. Depletion of myeloid-derived suppressor cells (MDSCs) reduced EcoHIV infection and boosted T cell responses. INTERPRETATION: This study provides an overview of the temporal interplay of persistent virus, DCs, MDSCs and antigen-specific CD8+T cells during acute infection. We identify MDSCs as critical gatekeepers that restrain antiviral T cell memory responses, and highlight MDSCs as an important target for developing effective vaccines against chronic human infections. FUNDING: Hong Kong Research Grant Council (T11-709/18-N, HKU5/CRF/13G), General Research Fund (17122915 and 17114114), Hong Kong Health and Medical Research Fund (11100752, 14130582, 16150662), Grant RGC-ANR A-HKU709/14, the San-Ming Project of Medicine (SZSM201512029), University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to HKU AIDS Institute.

Lack of the E3 Ubiquitin Ligase March1 Affects CD8 T Cell Fate and Exacerbates Insulin Resistance in Obese Mice.

Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. However, the mechanisms that trigger the underlying adipose tissues inflammation are not completely understood. Here, we show that the E3 ubiquitin ligase March1 controls the phenotypic and functional properties of CD8+ T cells in mice white adipose tissue. In a diet-induced obesity model, mice lacking March1 [March1 knockout (KO)] show increased insulin resistance compared to their WT counterparts. Also, in obese March1 KO mice, the proportions of effector/memory (Tem) and resident/memory (Trm) CD8+ T cells were higher in the visceral adipose tissue, but not in the spleen. The effect of March1 on insulin resistance and on the phenotype of adipose tissue CD8+ T cells was independent of major histocompatibility complex class II ubiquitination. Interestingly, we adoptively transferred either WT or March1 KO splenic CD8+ T cells into obese WT chimeras that had been reconstituted with Rag1-deficient bone marrow. We observed an enrichment of Tem and Trm cells and exacerbated insulin resistance in mice that received March1 KO CD8 T cells. Mechanistically, we found that March1 deficiency alters the metabolic activity of CD8+ T cells. Our results provide additional evidence of the involvement of CD8+ T cells in adipose tissue inflammation and suggest that March1 controls the metabolic reprogramming of these cells.

Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+ T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia.

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 TCRß 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.

You Shall Not Pass: Memory CD8 T Cells in Liver-Stage Malaria.

Each year over 200 million malaria infections occur, with over 400 000 associated deaths. Vaccines formed with attenuated whole parasites can induce protective memory CD8 T cell responses against liver-stage malaria; however, widespread administration of such vaccines is logistically challenging. Recent scientific findings are delineating how protective memory CD8 T cell populations are primed and maintained and how such cells mediate immunity to liver-stage malaria. Memory CD8 T cell anatomic localization and expression of transcription factors, homing receptors, and signaling molecules appear to play integral roles in protective immunity to liver-stage malaria. Further investigation of how such factors contribute to optimal protective memory CD8 T cell generation and maintenance in humans will inform efforts for improved vaccines.

Regulation of global CD8+ T-cell positioning by the actomyosin cytoskeleton.

CD8+ T cells have evolved as one of the most motile mammalian cell types, designed to continuously scan peptide-major histocompatibility complexes class I on the surfaces of other cells. Chemoattractants and adhesion molecules direct CD8+ T-cell homing to and migration within secondary lymphoid organs, where these cells colocalize with antigen-presenting dendritic cells in confined tissue volumes. CD8+ T-cell activation induces a switch to infiltration of non-lymphoid tissue (NLT), which differ in their topology and biophysical properties from lymphoid tissue. Here, we provide a short overview on regulation of organism-wide trafficking patterns during naive T-cell recirculation and their switch to non-lymphoid tissue homing during activation. The migratory lifestyle of CD8+ T cells is regulated by their actomyosin cytoskeleton, which translates chemical signals from surface receptors into mechanical work. We explore how properties of the actomyosin cytoskeleton and its regulators affect CD8+ T cell function in lymphoid and non-lymphoid tissue, combining recent findings in the field of cell migration and actin network regulation with tissue anatomy. Finally, we hypothesize that under certain conditions, intrinsic regulation of actomyosin dynamics may render NLT CD8+ T-cell populations less dependent on input from extrinsic signals during tissue scanning.

mTOR Signaling pathway as a master regulator of memory CD8+ T-cells, Th17, and NK cells development and their functional properties.

The mammalian target of rapamycin (mTOR) is a member of the evolutionary phosphatidylinositol kinase-related kinases (PIKKs). mTOR plays a pivotal role in the regulation of diverse aspects of cellular physiology such as body metabolism, cell growth, protein synthesis, cell size, autophagy, and cell differentiation. Immunologically, mTOR has a fundamental part in controlling and shaping diverse functions of innate and adaptive immune cells, in particular, T-cell subsets differentiation, survival, and metabolic reprogramming to ultimately regulate the fate of diverse immune cell types. Researchers report that rapamycin, a selective mTOR inhibitor, and immunosuppressive agent, has surprising immunostimulatory effects on inducing both quantitative and qualitative aspects of virus-specific memory CD8+ T-cells differentiation and homeostasis in a T-cell-intrinsic manner. The mTOR signaling pathway also plays a critical role in dictating the outcome of regulatory T cells (Treg), T helper 17 (Th17) cells, and natural killer (NK) cells proliferation and maturation, as well as the effector functions and cytotoxic properties of NK cells. Manipulation of mTOR activity is a critical therapeutic approach for pharmacological agents that seek to inhibit mTOR. This approach should enhance specific memory CD8 + T-cells responses and induce fully functional effector properties of NK cells to provoke their antitumor and antiviral activities.

Cytomegalovirus infection and progressive differentiation of effector-memory T cells.

Primary cytomegalovirus (CMV) infection leads to strong innate and adaptive immune responses against the virus, which prevents serious disease. However, CMV infection can cause serious morbidity and mortality in individuals who are immunocompromised. The adaptive immune response to CMV is characterized by large populations of effector-memory (EM) T cells that are maintained lifelong, a process termed memory inflation. Recent findings indicate that infection with CMV leads to continuous differentiation of CMV-specific EM-like T cells and that high-dose infection accelerates this progression. Whether measures that counteract CMV infection, such as anti-viral drugs, targeting of latently infected cells, adoptive transfer of CMV-specific T cells, and vaccination strategies, are able to impact the progressive differentiation of CMV-specific EM-like cells is discussed.