Virtual Memory CD8 Research Articles

The role of virtual memory CD8+ T cells in pulmonary viral and bacterial infection

Abstract Virtual memory CD8+ T (TVM) cells, also known as antigen-inexperienced T cells with memory phenotypes, have been reported to mediate bystander protection against primary infection. It is known that the expansion of TVM cells depends largely on IL-4; thus, we used α-galactosylceramide (α-GalCer), which activates invariant natural killer T (iNKT) cells to trigger a strong IL-4 response to expand TVM cells in mice. Whether expanded TVM cells could grant protection against influenza A virus (IAV) and Streptococcus pneumoniae (SPN) infections and the functions of TVM cells in the lungs in these settings remain unknown. Here, we revealed that TVM cells significantly increased in the respiratory tract after α-GalCer treatment and maintained for at least 14 days. In contrast, the percentage of iNKT cells has returned to basal levels at this time. Furthermore, α-GalCer treatment generated more effector functional CD8+ cells and the proportion of TVM cells in the cytokine-producing CD8+ cell population significantly increased in the lungs and mediastinal lymph nodes. Notably, α-GalCer treatment decreased the viral titer after mice were challenged with a high dose of IAV as well as significantly improved the survival of SPN-infected mice. These results suggested that the protection may be attributed to TVM cells. Therefore, we further established a reliable intranasal transfer model to investigate the direct role of TVM cells in pulmonary viral and bacterial infections.

A virtual memory T cell–originated CD44s-hiCD49dlo CD8+ T cell subset confers immune protection against respiratory viral infections

Abstract Virtual memory CD8+ T (TVM) cells, exhibiting a memory phenotype without foreign antigen exposure, exert protective immunity against viral and bacterial infections. However, a TVM-originated distinct CD8+ T cell subset (CD44super-hi (s-hi)CD49dlo CD8+ T cells) induces pathogenesis of a chronic inflammatory disease (alopecia areata (AA)) by NKG2D-mediated innate-like cytotoxicity (Nat. Immunol. 24(8):1308-17 (2023)). Notably, these pathogenic cells were also residing in the lungs. Therefore, in this study, we aimed to investigate the distinct immune characteristics of lung-infiltrated CD44s-hiCD49dlo CD8+ T cells in AA mice and their protective roles against respiratory viral infections. In AA mice, the lung-infiltrated CD44s-hiCD49dlo CD8+ T cells exhibited tissue-resident features, lower NKG2D expression, and less cytotoxicity than those in the skin. In AA mice with influenza A virus infection, the lung CD44s-hiCD49dlo CD8+ T cells showed increased NKG2D expression and cytotoxicity. Finally, CD44s-hiCD49dlo CD8+ T cells in the lungs of AA mice conferred immune protection against influenza virus infection, evidenced by a significantly improved survival rate and less body-weight loss. Collectively, our results elucidate the two-sided roles of TVM cells. The ambivalent aspects of CD44s-hiCD49dlo CD8+ T cells originated from TVM cells provide a solid rationale for the continuing investigation of TVM cells in immune protection and disease.

FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors

BackgroundPrevious research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells.MethodsAlbumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells.ResultsCD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells.ConclusionsThese findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

IL-4/IL-4 Ab complex enhances the accumulation of both antigen-specific and bystander CD8 T cells in mouse lungs infected with influenza A virus

BackgroundUnlike conventional T cells, innate and virtual-memory CD8 T cells in naïve mice acquire their memory phenotypes and functions in the absence of antigenic encounters in a cytokine-dependent manner. The relevant cytokines include interleukin-4 (IL-4), type I interferon, and interleukin-15 (IL-15). Moreover, exogenous IL-4 can also induce de novo generation and/or expansion of the virtual-memory CD8 T cell population. In this study, we investigated whether exogenous IL-4 could enhance the immune response to a viral infection.ResultsIn vivo administration of IL-4 and an anti-IL-4 antibody complex (IL-4C) increased CXCR3 expression in both memory and naïve phenotype CD8 T cells in the absence of antigenic stimulation, and protected mice from lethal influenza infection. Flow cytometric analysis of lung-infiltrating immune cells on day 5 after virus infection revealed higher numbers of antigen-specific and bystander CD8 T cells in IL-4C-treated mice than in control mice. In particular, the bystander CD8 T cells were a naïve or evident memory phenotypes. Crucially, an anti-CXCR3 blocking antibody abrogated this IL-4C effect, reflecting that the increased accumulation of CD8 T cells in the lungs after IL-4C treatment is dependent on CXCR3.ConclusionsThese data demonstrate that exogenous IL-4C plays a protective role by enhancing CXCR3-dependent migration of CD8 T cells into influenza-infected lungs.

Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.

A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity.

Virtual memory T (TVM) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although TVM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a TVM cell-originated CD44super-high(s-hi)CD49dlo CD8+ T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8+ TVM cells and can cause alopecia areata. Mechanistically, CD44s-hiCD49dlo CD8+ T cells could be induced from conventional TVM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.

Helminth Infection-Induced Increase in Virtual Memory CD8 T Cells Is Transient, Driven by IL-15, and Absent in Aged Mice.

CD8 virtual memory T (TVM) cells are Ag-naive CD8 T cells that have undergone partial differentiation in response to common γ-chain cytokines, particularly IL-15 and IL-4. TVM cells from young individuals are highly proliferative in response to TCR and cytokine stimulation but, with age, they lose TCR-mediated proliferative capacity and exhibit hallmarks of senescence. Helminth infection can drive an increase in TVM cells, which is associated with improved pathogen clearance during subsequent infectious challenge in young mice. Given the cytokine-dependent profile of TVM cells and their age-associated dysfunction, we traced proliferative and functional changes in TVM cells, compared with true naive CD8 T cells, after helminth infection of young and aged C57BL/6 mice. We show that IL-15 is essential for the helminth-induced increase in TVM cells, which is driven only by proliferation of existing TVM cells, with negligible contribution from true naive cell differentiation. Additionally, TVM cells showed the greatest proliferation in response to helminth infection and IL-15 compared with other CD8 T cells. Furthermore, TVM cells from aged mice did not undergo expansion after helminth infection due to both TVM cell-intrinsic and -extrinsic changes associated with aging.

Exploring the immunomodulatory role of virtual memory CD8+ T cells: Role of IFN gamma in tumor growth control.

Virtual memory CD8+ T cells (TVM) have been described as cells with a memory-like phenotype but without previous antigen (Ag) exposure. TVM cells have the ability to respond better to innate stimuli rather than by TCR engagement, producing large amounts of interferon gamma (IFNγ) after stimulation with interleukin (IL)-12 plus IL-18. As a result of the phenotypic similarity, TVM cells have been erroneously included in the central memory T cell subset for many years. However, they can now be discriminated via the CD49d receptor, which is up-regulated only on conventional memory T cells (TMEM) and effector T cells (TEFF) after specific cognate Ag recognition by a TCR. In this work we show that systemic expression of IL-12 plus IL-18 induced an alteration in the normal TVM vs TMEM/TEFF distribution in secondary lymphoid organs and a preferential enrichment of TVM cells in the melanoma (B16) and the pancreatic ductal adenocarcinoma(KPC) tumor models. Using our KPC bearing OT-I mouse model, we observed a significant increase in CD8+ T cell infiltrating the tumor islets after IL-12+IL-18 stimulation with a lower average speed when compared to those from control mice. This finding indicates a stronger interaction of T cells with tumor cells after cytokine stimulation. These results correlate with a significant reduction in tumor size in both tumor models in IL-12+IL-18-treated OT-I mice compared to control OT-I mice. Interestingly, the absence of IFNγ completely abolished the high antitumor capacity induced by IL-12+IL-18 expression, indicating an important role for these cytokines in early tumor growth control. Thus, our studies provide significant new information that indicates an important role of TVM cells in the immune response against cancer.

Virtual Memory CD8+ T Cells: Origin and Beyond.

The presence of CD8+ T cells with a memory phenotype in nonimmunized mice has been noted for decades, but it was not until about 2 decades ago that they began to be studied in greater depth. Currently called virtual memory CD8+ T cells, they consist of a heterogeneous group of cells with memory characteristics, without any previous contact with their specific antigens. These cells were identified in mice, but a few years ago, a cell type with characteristics equivalent to the murine ones was described in healthy humans. In this review, we address the different aspects of its biology mainly developed in murine models and what is currently known about its cellular equivalent in humans.

TLR2-induced CD8+ T-cell deactivation shapes dendritic cell differentiation in the bone marrow during sepsis.

Sepsis is associated with profound immune dysregulation that increases the risk for life-threatening secondary infections: Dendritic cells (DCs) undergo functional reprogramming due to yet unknown changes during differentiation in the bone marrow (BM). In parallel, lymphopenia and exhaustion of T lymphocytes interfere with antigen-specific adaptive immunity. We hypothesized that there exists a link between T cells and the modulation of DC differentiation in the BM during murine polymicrobial sepsis. Sepsis was induced by cecal ligation and puncture (CLP), a model for human bacterial sepsis. At different time points after CLP, the BM and spleen were analyzed in terms of T-cell subpopulations, activation, and Interferon (IFN)-γ synthesis as well as the number of pre-DCs. BM-derived DCs were generated in vitro. We observed that naïve and virtual memory CD8+ T cells, but not CD4+ T cells, were activated in an antigen-independent manner and accumulated in the BM early after CLP, whereas lymphopenia was evident in the spleen. The number of pre-DCs strongly declined during acute sepsis in the BM and almost recovered by day 4 after CLP, which required the presence of CD8+ T cells. Adoptive transfer experiments and in vitro studies with purified T cells revealed that Toll-like receptor 2 (TLR2) signaling in CD8+ T cells suppressed their capacity to secrete IFN-γ and was sufficient to change the transcriptome of the BM during sepsis. Moreover, the diminished IFN-γ production of CD8+ T cells favored the differentiation of DCs with increased production of the immune-activating cytokine Interleukin (IL)-12. These data identify a novel role of CD8+ T cells in the BM during sepsis as they sense TLR2 ligands and control the number and function of de novo differentiating DCs.

CCL5-Secreting Virtual Memory CD8+ T Cells Inversely Associate With Viral Reservoir Size in HIV-1-Infected Individuals on Antiretroviral Therapy.

Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (TCM) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (TEMRA). Moreover, a virtual memory CD8+ T cell (TVM) subset was enriched in CCL4-CCL5+ TEMRA cells and phenotypically distinctive from CCL4+ TCM subset, supported by single-cell RNA-Seq data. Specifically, TVM cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ TCM subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, TVM cells inhibited HIV-1 reactivation more effectively than non-TVM CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting TVM cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease.

Virtual memory T cells orchestrate extralymphoid responses conducive to resident memory.

A primary immune response is initiated in secondary lymphoid organs. Virtual memory CD8+ T (TVM) cells are antigen-inexperienced T cells of a central memory phenotype, acquired through self-antigen–driven homeostatic proliferation. Unexpectedly, we find that TVM cells are composed of CCR2+ and CCR2− subsets that differentially elaborate a spectrum of effector- and memory-poised functions directly in the tissue. During a primary influenza infection, TVM cells rapidly infiltrate the lungs in the first day after infection and promote early viral control. TVM cells that recognize viral antigen are retained in the tissue, clonally expand independent of secondary lymphoid organs, and give rise to tissue-resident memory cells. By orchestrating an extralymphoid primary response, heterogenous TVM cells bridge innate reaction and adaptive memory directly in the infected tissue.

Differential response of young and aged Virtual Memory CD8 T (TVM) cells to helminth-induced Th-2 cytokines

Abstract TVM cells are antigen-naïve, semi-differentiated CD8 T cells that develop in response to common γ (γc) chain cytokines, like IL-15 and IL-4. TVM cells respond more rapidly than conventional naïve CD8 T cells to antigen stimulation, thereby providing early control of viral and bacterial infections. TVM cells comprise 20% of the naive CD8 T cell pool in young mice but are selectively retained and make up to 50% of all antigenically naïve CD8 T cells in aged mice. In addition, aged TVM cells exhibit markers of senescence and lose proliferative capacity compared to young TVM cells. Recently, it was shown that IL-4 generated during helminth infection drove TVM cell expansion and improved pathogen clearance in subsequent infections. However, it is not known if the expanded subset is maintained with age or whether helminth infections similarly expand or improve the function of aged TVM cells. To evaluate this, we infected young mice with the helminth, Heligmosomoides polygyrus, and aged them to over 18 months. There was no difference in number or function of TVM cells in previously infected as compared to naïve aged mice. We then infected aged mice with helminths and observed no increase in TVM cell numbers, but there was a reduction in IFN-γ production by aged TVM cells. When naïve TVM cells were transferred to a young helminth infected host, proliferation of aged TVM cells was markedly reduced as compared to young TVM cells. Collectively these data suggest that, the protective effect of helminth infection in young mice, mediated by TVM cell expansion, is firstly not maintained into advanced age. Secondly, this effect cannot be generated in aged mice due to aged TVM cells being intrinsically less responsive to the helminth-induced cytokine environment.

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

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. The scientific literature on this issue was searched on PubMed. 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. 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.

MHC class I-independent activation of virtual memory CD8 T cells induced by chemotherapeutic agent-treated cancer cells.

Cancer cells can evade immune recognition by losing major histocompatibility complex (MHC) class I. Hence, MHC class I-negative cancers represent the most challenging cancers to treat. Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment. However, it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class I and whether such MHC class I-independent CD8 T-cell activation can be exploited for cancer immunotherapy. Here, we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class I-independent manner and that these activated CD8 T cells exhibit virtual memory (VM) phenotypes. Consistently, in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells. Mechanistically, MHC class I-independent activation of CD8 T cells requires cell-cell contact and activation of the PI3K pathway. VM CD8 T cells contribute to a superior therapeutic effect on MHC class I-deficient tumors. Using humanized mouse models or primary human CD8 T cells, we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class I. In conclusion, CD8 T cells can be directly activated in an MHC class I-independent manner by chemotherapy-treated cancers, and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class I-deficient cancers.

Activation of virtual memory CD8+ T cells specific for self antigens requires antigen presentation by CD11c+ cells

Abstract Even in experimentally naïve mice, a significant fraction of CD8+ T cells express CD44, a marker associated with previous exposure to cognate antigen. Many of these cells express additional hallmarks of the memory phenotype, leading to questions about their specificity, development, and functional relevance. It has been suggested that lymphopenic conditions experienced by early T cells in prenatal/neonatal mice can give rise to these unexpected “virtual” memory T cells. However, their antigen specificity remains largely unknown. Here, we report several peptide sequences derived from self antigens, which are capable of eliciting robust interferon gamma (IFNγ) secretion in CD8+ T cells isolated from naïve mice. Only CD44+ (memory phenotype), and not CD44− (naïve phenotype) T cells show this unexpected self-reactivity, and the antigens are cross presented by professional antigen-presenting cells (pAPCs) but are not presented to T cells by non-pAPCs expressing these antigens. Interestingly, antigen donor cells pretreated with IFNγ also failed to stimulate these T cells. The implications of having such self-reactive memory-phenotype T cells in circulation remain unclear, although their role in autoimmunity and self-tolerance can be imagined. There is also the possibility that such responses are a manifestation of immunological nihilism.

Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition.

The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (TVM cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, TVM cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, TVM cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by TVM cells through KIR-mediated recognition. This study suggests that TVM cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.

DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8+ T Cell Compartment by Negatively Regulating Tonic TCR Triggering.

The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B, and NK cell activation. Surprisingly, we show in this study that certain immune functions of CD8+ T cells are enhanced in the absence of DOCK2. Dock2-deficient mice have a pronounced expansion of their memory T cell compartment. Bone marrow chimera and adoptive transfer studies indicate that these memory T cells develop in a cell-intrinsic manner following thymic egress. Transcriptional profiling, TCR repertoire analyses, and cell surface marker expression indicate that Dock2-deficient naive CD8+ T cells directly convert into virtual memory cells without clonal effector T cell expansion. This direct conversion to memory is associated with a selective increase in TCR sensitivity to self-peptide MHC in vivo and an enhanced response to weak agonist peptides ex vivo. In contrast, the response to strong agonist peptides remains unaltered in Dock2-deficient T cells. Collectively, these findings suggest that the regulation of the actin dynamics by DOCK2 enhances the threshold for entry into the virtual memory compartment by negatively regulating tonic TCR triggering in response to weak agonists.

Similar but different: virtual memory CD8 T cells as a memory-like cell population.

Immunological memory is a phenomenon where the immune system can respond more rapidly to pathogens and immunological challenges that it has previously encountered. It is defined by several key hallmarks. After an initial encounter, immune cells (1) expand and (2) differentiate to form memory cell populations. Memory cells are (3) long-lived and (4) facilitate more rapid immune responses to subsequent infection because of (i) an increase in cell number, (ii) a decrease in the signaling threshold required for entry into cell cycle or effector function and (iii) localization of cells to tissue sites for surveillance. Classically, immunological memory has been antigen specific but it is becoming apparent that mechanisms of immunological memory can be co-opted by innate or antigen-inexperienced immune cells to generate heterogeneity in immune responses. One such cell is the virtual memory CD8 T (TVM ) cell, which is a semi-differentiated but antigen-naïve CD8 T-cell population. This review will summarize current knowledge of how TVM cells are generated, their memory-like hallmarks, how they are maintained during steady state, infection and aging, and propose a model to integrate key signaling pathways during their generation.

Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44hiCD62LhiCXCR3hiCD49dlo TVM cells through direct IL-4 signaling in CD8+ T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8+ T cells, leading to a subsequently raised antigen-specific CD8+ T cell activation that enhances control of viral infection.