Immunotherapy during the acute SHIV infection of macaques confers long-term suppression of viremia

We report that combination bNAb immunotherapy initiated on day 3 post-infection (PI) maintained durable CD8⁺ T cell–mediated suppression of SHIV_AD8 viremia and preinoculation levels of CD4⁺ T cells in 9 of 13 treated monkeys during nearly 6 yr of observation, as assessed by successive CD8⁺ T cell–depletion experiments. In an extension of that study, two treatment interventions (bNAbs alone or cART plus bNAbs) beginning on week 2 PI were conducted and conferred controller status to 7 of 12 monkeys that was also dependent on control mediated by CD8⁺ cells. However, the median time to suppression of plasma viremia following intervention on week 2 was markedly delayed (85 wk) compared with combination bNAb immunotherapy initiated on day 3 (39 wk). In both cases, the principal correlate of virus control was the induction of CD8⁺ T cellular immunity.     

HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death

Human T cell leukemia virus type 1 (HTLV-1) infects both CD4⁺ and CD8⁺ lymphocytes, yet it induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4⁺ phenotype. Here we show that in vivo infected CD4⁺ and CD8⁺ T cells displayed similar patterns of clonal expansion in carriers without malignancy. Cloned infected cells from individuals without malignancy had a dramatic increase in spontaneous proliferation, which predominated in CD8⁺ lymphocytes and depended on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1–positive CD8⁺ and CD4⁺ lymphocytes relied on 2 distinct mechanisms — infection prevented cell death in the former while recruiting the latter into the cell cycle. Cell cycling, but not apoptosis, depended on the level of viral-encoded tax expression. Infected tax-expressing CD4⁺ lymphocytes accumulated cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4⁺ infected clones.     

Fusion of HCV Nonstructural Antigen to MHC Class II–associated Invariant Chain Enhances T-cell Responses Induced by Vectored Vaccines in Nonhuman Primates

Despite viral vectors being potent inducers of antigen-specific T cells, strategies to further improve their immunogenicity are actively pursued. Of the numerous approaches investigated, fusion of the encoded antigen to major histocompatibility complex class II–associated invariant chain (Ii) has been reported to enhance CD8⁺ T-cell responses. We have previously shown that adenovirus vaccine encoding nonstructural (NS) hepatitis C virus (HCV) proteins induces potent T-cell responses in humans. However, even higher T-cell responses might be required to achieve efficacy against different HCV genotypes or therapeutic effect in chronically infected HCV patients. In this study, we assessed fusion of the HCV NS antigen to murine and human Ii expressed by the chimpanzee adenovirus vector ChAd3 or recombinant modified vaccinia Ankara in mice and nonhuman primates (NHPs). A dramatic increase was observed in outbred mice in which vaccination with ChAd3 expressing the fusion antigen resulted in a 10-fold increase in interferon-γ⁺ CD8⁺ T cells. In NHPs, CD8⁺ T-cell responses were enhanced and accelerated with vectors encoding the Ii-fused antigen. These data show for the first time that the enhancement induced by vector vaccines encoding li-fused antigen was not species specific and can be translated from mice to NHPs, opening the way for testing in humans.     

Temporal and spatial characterization of negative regulatory T cells in HIV‐infected/AIDS patients raises new diagnostic markers and therapeutic strategies

BackgroundNegative regulatory T cells (Tregs) not only deplete effector T cells but also inhibit the clearance of HIV during infection, which may allow Tregs to be used as informative diagnostic markers. To facilitate both diagnosis and treatment, a thorough understanding of these regulators by characterizing them on temporal and spatial scales is strongly required.MethodsHundred HIV‐infected/AIDS patients, including 87 males, with an average age of 35.8 years, as well as 20 healthy controls, were enrolled. Flow cytometry was used to analyze CD3+T cells, CD4+T cells, and CD8+T cells to evaluate the immune status of the participants. Then, a group of representative negative regulatory T cells, including CD4+PD‐1+T cells, CD4+PD‐1^highT cells, CD8+PD‐1+T cells, and CD4+CD25^high Tregs was also analyzed to explore their effects on disease progression and intercorrelation.ResultsThe percentages of CD4⁺PD‐1⁺T cells and CD4⁺CD25^highTregs increased in patients with the same ultrahigh significance. Temporally, the patients with both intermediate‐stage and late‐stage disease had higher percentages of CD4⁺PD‐1⁺T cells; however, the percentage of CD4⁺CD25^highTregs only increased in the patients with late‐stage disease. In addition, CD4⁺PD‐1⁺T cells but not CD4⁺CD25^highTregs were negatively correlated with the absolute CD4⁺T cell count. Spatially, no correlations between CD4⁺PD‐1⁺T cells and CD4⁺CD25^highTregs were observed, which suggests these Tregs function differently during immunosuppression.ConclusionsThis study characterized negative regulatory T cells in HIV‐infected/AIDS patients at both temporal and spatial scales and found that CD4⁺CD25⁺Tregs and CD4⁺PD‐1⁺T cells could be used as potential diagnostic markers for identifying different disease stages and monitoring disease progression.     

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

Memory and naive CD8⁺ T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8⁺ T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8⁺ T cell trafficking are largely unknown. Here, using murine models of infection and T cell transfer, we found that memory but not naive CD8⁺ T cells dynamically regulate expression of core 2 O-glycans, which interact with P- and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8⁺ T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8⁺ T cells. After unrelated infection or inflammatory challenge, memory CD8⁺ T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CD8⁺ T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8⁺ T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15–dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8⁺ T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These findings suggest that CD8⁺ memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy.     

Inflammatory IL-15 is required for optimal memory T cell responses

Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8⁺ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8⁺ T cells with a proliferation advantage over naive CD8⁺ T cells, suggesting that cell-extrinsic factors enhance memory CD8⁺ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8⁺ T cells following infection. Using murine models of viral infection and antigen exposure, we found that type I IFN–driven expression of IL-15 in response to viral infection prepares memory CD8⁺ T cells for rapid division independently of antigen reexposure by transiently inducing cell-cycle progression via a pathway dependent on mTOR complex-1 (mTORC1). Moreover, exposure to IL-15 allowed more rapid division of memory CD8⁺ T cells following antigen encounter and enhanced their protective capacity against viral infection. Together, these data reveal that inflammatory IL-15 promotes optimal responses by memory CD8⁺ T cells.     

Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected,ART-treated Nonhuman Primates

Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34⁺ cells expressing the mC46 anti-HIV fusion protein. We show that SHIV⁺, ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34⁺ cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV⁺, ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4⁺ T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4⁺CCR5⁺T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.     

Clinical impact of Fn-induced high expression of KIR2DL1 in CD8 T lymphocytes in oesophageal squamous cell carcinoma

BackgroundTo analyze the correlation between the inducing effect of Fusobacterium nucleatum (Fn) on the surface expression of the inhibitory receptor KIR2DL1 on CD8⁺ T cells in oesophageal squamous cell carcinoma (ESCC) and the clinicopathological features and survival prognosis and to explore its clinical significance.MethodsThe inducing effect of Fn on CD8⁺ T cell surface inhibitory receptor KIR2DL1 expression was analyzed in a coculture system of human CD8⁺ T cells and ESCC cells infected with Fn. Fn infection and the expression of KIR2DL1 on CD8⁺ T cells were detected by RNAscope and immunohistochemistry in ESCC tissues, and the correlations between the inducing effect of Fn on KIR2DL1 expression on CD8⁺ T cells and clinicopathological features were analyzed. COX regression was used to analyze the influence of each factor on the prognosis of ESCC. Survival curves were plotted by the Kaplan–Meier method, and the effect of KIR2DL1 induction on survival time was analyzed by the log-rank test.ResultsIn the coculture system, KIR2DL1 expression on the surface of CD8⁺ T cells increased with increasing Fn infection time. In ESCC tissues, Fn infection was significantly correlated with high KIR2DL1 expression on CD8⁺ T cells. The Fn + CD8⁺KIR2DL1 positive patients were predominantly males who were smokers and alcohol drinkers. Moreover, patients with Fn infection were characterized by poor tumour differentiation, advanced clinical stage, and a short survival time. Meanwhile, Fn + CD8⁺KIR2DL1 positive group was independent risk factor affecting the prognosis of ESCC patients.ConclusionsLong-term drinking and smoking lead to an extremely unhealthy oral environment in which Fn infection and colonization are more likely to occur, thus inducing high expression of KIR2DL1 on the surface of CD8⁺ T cells, which can weaken the antitumour immune response and promote the malignant progression of ESCC.

HIGHLIGHTS

• Fn induced high expression of KIR2DL1 CD8⁺ T cells in a time-dependent manner.
• Fn can reduce the response of tumour cells to CDDP.
• The inducing effect of Fn on CD8⁺ T cell surface KIR2DL1 expression was significantly associated with the poor prognosis of ESCC patients.

     

An Alternate Pathway for T Cell Development Supported by the Bone Marrow Microenvironment: Recapitulation of Thymic Maturation

In the principal pathway of α/β T cell maturation, T cell precursors from the bone marrow migrate to the thymus and proceed through several well-characterized developmental stages into mature CD4⁺ and CD8⁺ T cells. This study demonstrates an alternative pathway in which the bone marrow microenvironment also supports the differentiation of T cell precursors into CD4⁺ and CD8⁺ T cells. The marrow pathway recapitulates developmental stages of thymic maturation including a CD4⁺CD8⁺ intermediary cell and positive and negative selection, and is strongly inhibited by the presence of mature T cells. The contribution of the marrow pathway in vivo requires further study in mice with normal and deficient thymic or immune function.     

CD8⁺ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung

The human lung T cell compartment contains many CD8⁺ T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8⁺ T cells expressing CD103 (αE integrin) resides. Here, we determined the specificity and function of CD103⁺CD8⁺ T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103⁺CD8⁺ T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8⁺ T cells specific for influenza but not in those specific for EBV or CMV. CD103⁺ and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8⁺ T cell cytotoxic function. In contrast to CD103^–CD8⁺ T cells, most CD103⁺CD8⁺ cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier.     

HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

CD8⁺ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E–restricted CD8⁺ T cell responses in HIV infection, however, remains unknown. In this study, CD8⁺ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E–restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8⁺ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8⁺ T cells. Importantly, bulk CD8⁺ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E–restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E–restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8⁺ T cell responses in HIV infection.     

Liver-resident CD8+ T cells in viral hepatitis: not always good guys

More than twenty years ago, non–HBV-specific CD8⁺ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8⁺ T cells were noted to contribute to viral control. The role of HBV-specific CD8⁺ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8⁺ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8⁺ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8⁺ T cells.     

Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells

Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4⁺ and CD8⁺ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8⁺ T cells is qualitatively different from that in CD4⁺ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8⁺ T cells, whereas those in CD4⁺ T cells were intact. PLCβ4-deficient CD8⁺ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP₃ generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8⁺ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8⁺ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4⁺ and CD8⁺ T cells and selectively promotes CD8⁺ T cell–dependent adaptive immunity.     

Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses

The induction of persistent intraepithelial CD8⁺ T cell responses may be key to the development of vaccines against mucosally transmitted pathogens, particularly for sexually transmitted diseases. Here we investigated CD8⁺ T cell responses in the female mouse cervicovaginal mucosa after intravaginal immunization with human papillomavirus vectors (HPV pseudoviruses) that transiently expressed a model antigen, respiratory syncytial virus (RSV) M/M2, in cervicovaginal keratinocytes. An HPV intravaginal prime/boost with different HPV serotypes induced 10-fold more cervicovaginal antigen-specific CD8⁺ T cells than priming alone. Antigen-specific T cell numbers decreased only 2-fold after 6 months. Most genital antigen-specific CD8⁺ T cells were intra- or subepithelial, expressed α_E-integrin CD103, produced IFN-γ and TNF-α, and displayed in vivo cytotoxicity. Using a sphingosine-1-phosphate analog (FTY720), we found that the primed CD8⁺ T cells proliferated in the cervicovaginal mucosa upon HPV intravaginal boost. Intravaginal HPV prime/boost reduced cervicovaginal viral titers 1,000-fold after intravaginal challenge with vaccinia virus expressing the CD8 epitope M2. In contrast, intramuscular prime/boost with an adenovirus type 5 vector induced a higher level of systemic CD8⁺ T cells but failed to induce intraepithelial CD103⁺CD8⁺ T cells or protect against recombinant vaccinia vaginal challenge. Thus, HPV vectors are attractive gene-delivery platforms for inducing durable intraepithelial cervicovaginal CD8⁺ T cell responses by promoting local proliferation and retention of primed antigen-specific CD8⁺ T cells.     

Permanent CD8+ T Cell Depletion Prevents Proteinuria in Active Heymann Nephritis

Active Heymann nephritis (HN) is a rat model of human idiopathic membranous nephropathy in which injury is thought to be mediated by membrane attack complex of complement (MAC) activated by antibody (Ab) to glomerular epithelial cells. Recent work has shown that HN develops in C6-deficient rats which cannot assemble MAC, and that infiltration of activated cytotoxic CD8⁺ T cells and macrophages into glomeruli coincides with proteinuria. This study examined the role of CD8⁺ T cells in mediating glomerular injury in HN by permanent CD8⁺ cytotoxic T cell depletion via adult thymectomy (ATx) and anti-CD8 mAb. Groups of rats were depleted of CD8⁺ T cells either before immunization for HN or 6 wk after immunization when Ab responses and glomerular IgG deposition were well established. These were compared with groups of HN, ATx/HN, and complete Freund''s adjuvant (CFA) controls. Neither group of CD8⁺ T cell–depleted rats developed proteinuria, although there was normal development and deposition of Ab. CD8⁺ T cell–depleted rats developed neither T cell or macrophage infiltrates nor their effector cytokines, which are present in glomeruli of rats with HN. Examination of lymph node (LN) draining sites of immunization showed these findings were not explained by altered immune events within these LNs. It was concluded that CD8⁺ cytotoxic T cells are essential to the mediation of glomerular injury in HN and may be relevant to the pathogenesis and treatment of membranous nephropathy.     

The route of priming influences the ability of respiratory virus–specific memory CD8+ T cells to be activated by residual antigen

After respiratory virus infections, memory CD8⁺ T cells are maintained in the lung airways by a process of continual recruitment. Previous studies have suggested that this process is controlled, at least in the initial weeks after virus clearance, by residual antigen in the lung-draining mediastinal lymph nodes (MLNs). We used mouse models of influenza and parainfluenza virus infection to show that intranasally (i.n.) primed memory CD8⁺ T cells possess a unique ability to be reactivated by residual antigen in the MLN compared with intraperitoneally (i.p.) primed CD8⁺ T cells, resulting in the preferential recruitment of i.n.-primed memory CD8⁺ T cells to the lung airways. Furthermore, we demonstrate that the inability of i.p.-primed memory CD8⁺ T cells to access residual antigen can be corrected by a subsequent i.n. virus infection. Thus, two independent factors, initial CD8⁺ T cell priming in the MLN and prolonged presentation of residual antigen in the MLN, are required to maintain large numbers of antigen-specific memory CD8⁺ T cells in the lung airways.In recent years, there has been considerable progress in understanding the mechanisms regulating the tissue-specific migration of lymphocytes to peripheral sites. An evolving concept is that environmental factors at the site of initial priming induce the expression of tissue-selective homing molecules on activated lymphocytes. In support of this, numerous studies have demonstrated a pivotal role for antigen-presenting cells in the programming of lymphocyte trafficking patterns during priming (Mora et al., 2003; Iwata et al., 2004; Sigmundsdottir et al., 2007). In contrast, several recent studies suggest a pliable property of memory T cells in terms of their tissue tropism. Adoptive transfer and parabiosis studies have shown that the location of initial priming has little impact on the ability of circulating effector memory T cells (T_EMs) to migrate to different nonlymphoid sites (Klonowski et al., 2004; Masopust et al., 2004). One explanation for this pleotropic homing ability is that activated CD8⁺ T cells disseminate from LNs draining the site of infection to distant LNs, where they acquire additional tissue-homing molecules associated with the local microenvironment (Liu et al., 2006). Moreover, the migration of circulating central memory T cells (T_CMs) to nonlymphoid tissues also results in functional and phenotypic conversion to tissue-resident T_EM phenotype (Laouar et al., 2005, 2007; Kohlmeier et al., 2007; Marzo et al., 2007). Together, these studies demonstrate that the site of initial priming, the continued maturation of activated T cells in nondraining lymphoid tissues, and the local environment within nonlymphoid tissues all contribute the migratory properties of memory CD8⁺ T cells.Studies in both humans and mice have shown that substantial numbers of T_EM persist in the lung airways after the resolution of respiratory virus infections. The numbers of T_EM in the lung airways gradually decline over the first 6 mo after infection and then stabilize as a relatively small population of memory T cells that is maintained in the lung airways indefinitely (Ostler et al., 2001; Hogan et al., 2001a; Wiley et al., 2001; de Bree et al., 2005; van Panhuys et al., 2005). This decline and stabilization in the number of memory T cells in the lung airways correlates with a progressive decline in cell-mediated protection from a secondary challenge (Liang et al., 1994; Kündig et al., 1996; Hogan et al., 2001b; Ray et al., 2004; Bachmann et al., 2005a,b). Unlike memory T cell populations that reside in other anatomical locations, lung airway memory T cells are not directly maintained through cytokine-driven homeostatic proliferation within the lung airways. Rather, antigen-specific memory T cells present in the lung airways represent a dynamic population that is maintained by continual recruitment from the systemic memory T cell pool under steady-state conditions (Ely et al., 2006). The accumulation of memory T cells in the airways under steady-state conditions is determined by migration from the circulation and cell death within the airways, a process which we refer to as continual recruitment. A recent study has demonstrated that residual antigen is maintained in the local draining LNs for several months after respiratory virus infection, and it has suggested a model in which recent stimulation by residual antigen is required for continual recruitment of memory CD8⁺ T cells to the airways (Zammit et al., 2006). In addition, we previously demonstrated that systemic memory CD8⁺ T cells generated after a respiratory virus infection could migrate to the airways in the absence of cognate antigen, albeit at low levels (Kohlmeier et al., 2007). However, it is not known how the route of priming impacts the ability of these antigen-dependent and -independent mechanisms to promote the recruitment of memory CD8⁺ T cells to the lung airways.To better understand the mechanisms regulating the continual recruitment of memory CD8⁺ T cells to the lung airways, we investigated the localization of memory CD8⁺ T cells that had been elicited by intranasal (i.n.) versus i.p. infection. The data show that i.n.-primed memory CD8⁺ T cells were preferentially recruited and maintained in the lung airways compared with i.p.-primed CD8⁺ T cells, and the defective recruitment of i.p.-primed memory CD8⁺ T cells to the lung airways was not corrected by the presence of cognate residual antigen in the mediastinal LN (MLN). Importantly, the ability of virus-specific memory CD8⁺ T cells to be activated by residual antigen in the MLN was restricted to i.n.-primed cells, and this activation resulted in multiple phenotypic changes which are associated with lung airway-resident cells. Collectively, the data suggest that not only the prolonged presentation of cognate antigen in the MLN but also T cell priming in the LNs that drain the respiratory tract during the primary response are required for the continual recruitment of memory CD8⁺ T cells to the lung airways.     

CD4+ and CD8+ T cell–dependent antiviral immunity requires STIM1 and STIM2

Calcium signaling is critical for lymphocyte function, and intracellular Ca²⁺ concentrations are regulated by store-operated Ca²⁺ entry (SOCE) through Ca²⁺ release–activated Ca²⁺ (CRAC) channels. In patients, loss-of-function mutations in CRAC channel components ORAI1 and STIM1 abolish SOCE and are associated with recurrent and chronic viral infections. Here, using mice with conditional deletion of Stim1 and its homolog Stim2 in T cells, we determined that both components are required for the maintenance of virus-specific memory CD8⁺ T cells and recall responses following secondary infection. In the absence of STIM1 and STIM2, acute viral infections became chronic. Early during infection, STIM1 and STIM2 were required for the differentiation of naive CD8⁺ T cells into fully functional cytolytic effector cells and mediated the production of cytokines and prevented cellular exhaustion in viral-specific CD8⁺ effector T cells. Importantly, memory and recall responses by CD8⁺ T cells required expression of STIM1 and STIM2 in CD4⁺ T cells. CD4⁺ T cells lacking STIM1 and STIM2 were unable to provide “help” to CD8⁺ T cells due to aberrant regulation of CD40L expression. Together, our data indicate that STIM1, STIM2, and CRAC channel function play distinct but synergistic roles in CD4⁺ and CD8⁺ T cells during antiviral immunity.     

Treatment with Telbivudine Positively Regulates Antiviral Immune Profiles in Chinese Patients with Chronic Hepatitis B

Chronic infection with hepatitis B virus (HBV) is associated with impairment of T and NK cell immunity. This study was aimed at investigating the impact of treatment with telbivudine (LDT) on T and NK cell immunity in patients with chronic hepatitis B (CHB). A total of 54 CHB patients and 30 healthy controls (HC) were recruited. Individual patients were treated orally with 600 mg LDT daily for 13 months. The serum HBV DNA loads, the levels of the HBV-related biomarkers alanine aminotransferase (ALT) and aspartate transaminase (AST), and the numbers of different subsets of peripheral T and NK cells in subjects were measured before and longitudinally after LDT treatment. Following treatment with LDT, the serum HBV DNA loads and the percentages of HBsAg- or HBeAg-seropositive cases were gradually reduced, accompanied by decreased levels of serum ALT and AST. In comparison with the HC, fewer CD3⁻ CD56⁺ and CD244⁺ NK cells and CD3⁺ CD8⁺ T cells, lower frequencies of cytokine⁺ CD4⁺ T cells, and more CD3⁺ CD4⁺, CD4⁺ CD25⁺ Foxp3⁺, CD4⁺ CD25⁺ CD127^low, and CD8⁺ PD-1⁺ T cells were detected in CHB patients. Treatment with LDT increased the numbers of NK and CD8⁺ cells and the frequencies of cytokine⁺ CD4⁺ T cells but reduced the numbers of CD4⁺ CD25⁺ Foxp3⁺, CD4⁺ CD25⁺ CD127^low, and CD8⁺ PD-1⁺ T cells in CHB patients. The frequencies of cytokine⁺ CD4⁺ T cells were negatively associated with the levels of serum HBV DNA, ALT, and AST. Thus, treatment with LDT inhibits HBV replication, modulates T and NK cell immunity, and improves liver function in Chinese patients with CHB.