Ten Years of Newborn Screening for Severe Combined Immunodeficiency (SCID) in Massachusetts.

BACKGROUND: Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. OBJECTIVE: We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). METHODS: TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. RESULTS: NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. CONCLUSIONS: Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.

Green Principles for Vehicle Lightweighting.

A large portion of life cycle transportation impacts occur during vehicle operation, and key improvement strategies include increasing powertrain efficiency, vehicle electrification, and lightweighting vehicles by reducing their mass. The potential energy benefits of vehicle lightweighting are large, given that 29.5 EJ was used in all modes of U.S. transportation in 2016, and roughly half of the energy spent in wheeled transportation and the majority of energy spent in aircraft is used to move vehicle mass. We collect and review previous work on lightweighting, identify key parameters affecting vehicle environmental performance (e.g., vehicle mode, fuel type, material type, and recyclability), and propose a set of 10 principles, with examples, to guide environmental improvement of vehicle systems through lightweighting. These principles, based on a life cycle perspective and taken as a set, allow a wide range of stakeholders (designers, policy-makers, and vehicle manufacturers and their material and component suppliers) to evaluate the trade-offs inherent in these complex systems. This set of principles can be used to evaluate trade-offs between impact categories and to help avoid shifting of burdens to other life cycle phases in the process of improving use-phase environmental performance.

Revealing the nature of morphological changes in carbon nanotube-polymer saturable absorber under high-power laser irradiation.

Composites of single-walled carbon nanotubes (SWNTs) and water-soluble polymers (WSP) are the focus of significant worldwide research due to a number of applications in biotechnology and photonics, particularly for ultrashort pulse generation. Despite the unique possibility of constructing non-linear optical SWNT-WSP composites with controlled optical properties, their thermal degradation threshold and limit of operational power remain unexplored. In this study, we discover the nature of the SWNT-polyvinyl alcohol (PVA) film thermal degradation and evaluate the modification of the composite properties under continuous high-power ultrashort pulse laser operation. Using high-precision optical microscopy and micro-Raman spectroscopy, we have examined SWNT-PVA films before and after continuous laser radiation exposure (up to 40 hours) with a maximum optical fluence of 2.3 mJ·cm-2. We demonstrate that high-intensity laser radiation results in measurable changes in the composition and morphology of the SWNT-PVA film due to efficient heat transfer from SWNTs to the polymer matrix. The saturable absorber modification does not affect the laser operational performance. We anticipate our work to be a starting point for more sophisticated research aimed at the enhancement of SWNT-PVA films fabrication for their operation as reliable saturable absorbers in high-power ultrafast lasers.

Early Combination Antiretroviral Therapy Limits Exposure to HIV-1 Replication and Cell-Associated HIV-1 DNA Levels in Infants.

The primary aim of this study was to measure HIV-1 persistence following combination antiretroviral therapy (cART) in infants and children. Peripheral blood mononuclear cell (PBMC) HIV-1 DNA was quantified prior to and after 1 year of cART in 30 children, stratified by time of initiation (early, age <3 months, ET; late, age >3 months-2 years, LT). Pre-therapy PBMC HIV-1 DNA levels correlated with pre-therapy plasma HIV-1 levels (r = 0.59, p<0.001), remaining statistically significant (p = 0.002) after adjustment for prior perinatal antiretroviral exposure and age at cART initiation. PBMC HIV-1 DNA declined significantly after 1 year of cART (Overall: -0.91±0.08 log10 copies per million PBMC, p<0.001; ET: -1.04±0.11 log10 DNA copies per million PBMC, p<0.001; LT: -0.74 ±0.13 log10 DNA copies per million PBMC, p<0.001) but rates of decline did not differ significantly between ET and LT. HIV-1 replication exposure over the first 12 months of cART, estimated as area-under-the-curve (AUC) of circulating plasma HIV-1 RNA levels, was significantly associated with PBMC HIV-1 DNA at one year (r = 0.51, p = 0.004). In 21 children with sustained virologic suppression after 1 year of cART, PBMC HIV-1 DNA levels continued to decline between years 1 and 4 (slope -0.21 log10 DNA copies per million PBMC per year); decline slopes did not differ significantly between ET and LT. PBMC HIV-1 DNA levels at 1 year and 4 years of cART correlated with age at cART initiation (1 year: p = 0.04; 4 years: p = 0.03) and age at virologic control (1 and 4 years, p = 0.02). Altogether, these data indicate that reducing exposure to HIV-1 replication and younger age at cART initiation are associated with lower HIV-1 DNA levels at and after one year of age, supporting the concept that HIV-1 diagnosis and cART initiation in infants should occur as early as possible.

Impacts of Vehicle Weight Reduction via Material Substitution on Life-Cycle Greenhouse Gas Emissions.

This study examines the vehicle-cycle and vehicle total life-cycle impacts of substituting lightweight materials into vehicles. We determine part-based greenhouse gas (GHG) emission ratios by collecting material substitution data and evaluating that alongside known mass-based GHG ratios (using and updating Argonne National Laboratory's GREET model) associated with material pair substitutions. Several vehicle parts are lightweighted via material substitution, using substitution ratios from a U.S. Department of Energy report, to determine GHG emissions. We then examine fuel-cycle GHG reductions from lightweighting. The fuel reduction value methodology is applied using FRV estimates of 0.15-0.25, and 0.25-0.5 L/(100km·100 kg), with and without powertrain adjustments, respectively. GHG breakeven values are derived for both driving distance and material substitution ratio. While material substitution can reduce vehicle weight, it often increases vehicle-cycle GHGs. It is likely that replacing steel (the dominant vehicle material) with wrought aluminum, carbon fiber reinforced plastic (CRFP), or magnesium will increase vehicle-cycle GHGs. However, lifetime fuel economy benefits often outweigh the vehicle-cycle, resulting in a net total life-cycle GHG benefit. This is the case for steel replaced by wrought aluminum in all assumed cases, and for CFRP and magnesium except for high substitution ratio and low FRV.

Life Cycle Assessment of Vehicle Lightweighting: Novel Mathematical Methods to Estimate Use-Phase Fuel Consumption.

Lightweighting is a key strategy to improve vehicle fuel economy. Assessing the life-cycle benefits of lightweighting requires a quantitative description of the use-phase fuel consumption reduction associated with mass reduction. We present novel methods of estimating mass-induced fuel consumption (MIF) and fuel reduction values (FRVs) from fuel economy and dynamometer test data in the U.S. Environmental Protection Agency (EPA) database. In the past, FRVs have been measured using experimental testing. We demonstrate that FRVs can be mathematically derived from coast down coefficients in the EPA vehicle test database avoiding additional testing. MIF and FRVs calculated for 83 different 2013 MY vehicles are in the ranges 0.22-0.43 and 0.15-0.26 L/(100 km 100 kg), respectively, and increase to 0.27-0.53 L/(100 km 100 kg) with powertrain resizing to retain equivalent vehicle performance. We show how use-phase fuel consumption can be estimated using MIF and FRVs in life cycle assessments (LCAs) of vehicle lightweighting from total vehicle and vehicle component perspectives with, and without, powertrain resizing. The mass-induced fuel consumption model is illustrated by estimating lifecycle greenhouse gas (GHG) emission benefits from lightweighting a grille opening reinforcement component using magnesium or carbon fiber composite for 83 different vehicle models.

Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset.

Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon α treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.

Pilot study on the immunogenicity of paired Env immunogens from mother-to-child transmitted HIV-1 isolates.

Recent studies have reported that founder viruses play unique roles in establishing HIV-1 infection. Understanding the biological and immunological features of envelope glycoproteins (Env) from such viruses may facilitate the development of effective vaccines against HIV-1. In this report, we evaluated the immunogenicity of gp120 immunogens from two pairs of clade B and two pairs of clade C mother-to-child transmitted (MTCT) HIV-1 variants that had various levels of sensitivity to broadly neutralizing monoclonal antibodies. Individual gp120 DNA and protein vaccines were produced from each of the eight MTCT Env antigens included in the current study. Rabbits were immunized with these gp120 immunogens by the DNA prime-protein boost approach. High level Env-specific antibody responses were elicited by all MTCT gp120 immunogens. However, their abilities to elicit neutralizing antibody (NAb) responses differed and those from relatively neutralization-resistant variants tended to be more effective in eliciting broader NAb. Results of this pilot study indicated that not all MTCT Env proteins have the same potential to elicit NAb. Understanding the mechanism(s) behind such variation may provide useful information in formulating the next generation of HIV vaccines.

Genotypic and functional properties of early infant HIV-1 envelopes.

BACKGROUND: Understanding the properties of HIV-1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission. In this study, 162 full-length envelope (env) clones were generated from plasma RNA obtained from 5 HIV-1 Clade B infected mother-infant pairs. Following extensive genotypic and phylogenetic analyses, 35 representative clones were selected for functional studies. RESULTS: Infant quasispecies were highly homogeneous and generally represented minor maternal variants, consistent with transmission across a selective bottleneck. Infant clones did not differ from the maternal in env length, or glycosylation. All infant variants utilized the CCR5 co-receptor, but were not macrophage tropic. Relatively high levels (IC50 ≥ 100 µg/ml) of autologous maternal plasma IgG were required to neutralize maternal and infant viruses; however, all infant viruses were neutralized by pooled sera from HIV-1 infected individuals, implying that they were not inherently neutralization-resistant. All infant viruses were sensitive to the HIV-1 entry inhibitors Enfuvirtide and soluble CD4; none were resistant to Maraviroc. Sensitivity to human monoclonal antibodies 4E10, 2F5, b12 and 2G12 varied. CONCLUSIONS: This study provides extensive characterization of the genotypic and functional properties of HIV-1 env shortly after transmission. We present the first detailed comparisons of the macrophage tropism of infant and maternal env variants and their sensitivity to Maraviroc, the only CCR5 antagonist approved for therapeutic use. These findings may have implications for improving approaches to prevent mother-to-child HIV-1 transmission.

Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes.

Memory T cells cross-reactive with epitopes encoded by related or even unrelated viruses may alter the immune response and pathogenesis of infection by a process known as heterologous immunity. Because a challenge virus epitope may react with only a subset of the T cell repertoire in a cross-reactive epitope-specific memory pool, the vigorous cross-reactive response may be narrowly focused, or oligoclonal. We show in this article, by examining human T cell cross-reactivity between the HLA-A2-restricted influenza A virus-encoded M1(58-66) epitope (GILGFVFTL) and the dissimilar Epstein-Barr virus-encoded BMLF1(280-288) epitope (GLCTLVAML), that, under some conditions, heterologous immunity can lead to a significant broadening, rather than a narrowing, of the TCR repertoire. We suggest that dissimilar cross-reactive epitopes might generate a broad, rather than a narrow, T cell repertoire if there is a lack of dominant high-affinity clones; this hypothesis is supported by computer simulation.

Low-cost HIV-1 diagnosis and quantification in dried blood spots by real time PCR.

BACKGROUND: Rapid and cost-effective methods for HIV-1 diagnosis and viral load monitoring would greatly enhance the clinical management of HIV-1 infected adults and children in limited-resource settings. Recent recommendations to treat perinatally infected infants within the first year of life are feasible only if early diagnosis is routinely available. Dried blood spots (DBS) on filter paper are an easy and convenient way to collect and transport blood samples. A rapid and cost effective method to diagnose and quantify HIV-1 from DBS is urgently needed to facilitate early diagnosis of HIV-1 infection and monitoring of antiretroviral therapy. METHODS AND FINDINGS: We have developed a real-time LightCycler (rtLC) PCR assay to detect and quantify HIV-1 from DBS. HIV-1 RNA extracted from DBS was amplified in a one-step, single-tube system using primers specific for long-terminal repeat sequences that are conserved across all HIV-1 clades. SYBR Green dye was used to quantify PCR amplicons and HIV-1 RNA copy numbers were determined from a standard curve generated using serially diluted known copies of HIV-1 RNA. This assay detected samples across clades, has a dynamic range of 5 log(10), and %CV <8% up to 4 log(10) dilution. Plasma HIV-1 RNA copy numbers obtained using this method correlated well with the Roche Ultrasensitive (r = 0.91) and branched DNA (r = 0.89) assays. The lower limit of detection (95%) was estimated to be 136 copies. The rtLC DBS assay was 2.5 fold rapid as well as 40-fold cheaper when compared to commercial assays. Adaptation of the assay into other real-time systems demonstrated similar performance. CONCLUSIONS: The accuracy, reliability, genotype inclusivity and affordability, along with the small volumes of blood required for the assay suggest that the rtLC DBS assay will be useful for early diagnosis and monitoring of pediatric HIV-1 infection in resource-limited settings.

Safety and immunogenicity of recombinant poxvirus HIV-1 vaccines in young adults on highly active antiretroviral therapy.

A trial to evaluate the safety and immunogenicity of recombinant modified vaccinia Ankara (MVA) and fowlpox (FP) vectors expressing multiple HIV-1 proteins was conducted in twenty HIV-1 infected youth with suppressed viral replication on HAART. The MVA and FP-based multigene HIV-1 vaccines were safe and well tolerated. Increased frequencies of HIV-1 specific CD4+ proliferative responses and cytokine secreting cells were detected following immunization. Increased frequencies and breadth of HIV-1 specific CD8 T-cell responses were also detected. Plasma HIV-1-specific antibody levels and neutralizing activity were unchanged following vaccination. Poxvirus-based vaccines may merit further study in therapeutic vaccine protocols.

On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis.

Memory B cells latently infected with Epstein-Barr virus (mB(Lats)) in the blood disappear rapidly on presentation with acute symptomatic primary infection (acute infectious mononucleosis [AIM]). They undergo a simple exponential decay (average half-life: 7.5 +/- 3.7 days) similar to that of normal memory B cells. The cytotoxic T lymphocyte (CTL) response to immediate early (IE) lytic antigens (CTL(IEs)) also decays over this time period, but no such correlation was observed for the CTL response to lytic or latent antigens or to the levels of virions shed into saliva. We have estimated the average half-life of CTL(IEs) to be 73 (+/- 23) days. We propose that cycles of infection and reactivation occur in the initial stages of infection that produce high levels of mB(Lats) in the circulation. Eventually the immune response arises and minimizes these cycles leaving the high levels of mB(Lats) in the blood to decay through simple memory B-cell homeostasis mechanisms. This triggers the cells to reactivate the virus whereupon most are killed by CTL(IEs) before they can release virus and infect new cells. The release of antigens caused by this large-scale destruction of infected cells may trigger the symptoms of AIM and be a cofactor in other AIM-associated diseases.

Influence of EBV on the peripheral blood memory B cell compartment.

Peripheral blood memory B cells latently infected with EBV bear somatic mutations and are typically isotype switched consistent with being classical Ag-selected memory B cells. In this work, we performed a comparative analysis of the expressed Ig genes between large sets of EBV-infected and uninfected peripheral blood B cells, isolated from the same infectious mononucleosis patients, to determine whether differences exist that could reveal the influence of EBV on the production and maintenance of these cells. We observed that EBV(+) cells on average accumulated more somatic hypermutations than EBV(-) cells. In addition, they had more replacement mutations and a higher replacement-silent ratio of mutations in their CDRs. We also found that EBV occupies a skewed niche within the memory compartment, due to its exclusion from the CD27(+)IgD(+)IgM(+) subset, but this skewing does not affect the overall structure of the compartment. These results indicate that EBV impacts the mutation and selection process of infected cells but that once they enter memory they cannot be distinguished from uninfected cells by host homeostasis mechanisms.

Characteristics and management of HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the USA.

BACKGROUND: Rates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT. METHODS: In this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression. RESULTS: In Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections. More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery. CONCLUSION: These findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain. TRIAL REGISTRATION: NCT00000869.

Vaccines to prevent transmission of HIV-1 via breastmilk: scientific and logistical priorities.

Mother-to-child transmission (MTCT) of HIV-1 is the major mode of paediatric infection. The rapidly increasing incidence of MTCT worldwide has resulted in an urgent need for preventive strategies. Antiretroviral regimens can prevent intrapartum HIV transmission; however, these regimens do not prevent HIV transmission through breastfeeding. Furthermore, children who escape MTCT are again at risk of infection when they become sexually active as adolescents. An infant vaccine regimen, begun at birth, would hence be a more attractive strategy and might also provide the basis for lifetime protection. Unique features of MTCT and paediatric HIV disease could be helpful in understanding correlates of immune protection and could facilitate rapid assessment of vaccine efficacy. Thus, there is compelling rationale to develop safe, effective HIV vaccines for use in infants and children. Here, we discuss the scientific and logistical challenges for the development of paediatric HIV vaccines; available vaccines and completed or planned paediatric vaccine trials are also discussed.

Therapy with a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody reduces disease severity and viral burden in golden Syrian hamsters.

BACKGROUND: Immunotherapy with monoclonal antibodies (MAbs) offers safe interventions for the prevention of infection in patients after organ transplantation and for the treatment of cancers and autoimmune diseases. MAb 201 is a severe acute respiratory syndrome-associated coronavirus (SARS-CoV)-specific MAb that prevents establishment of viral replication in vitro and prevents viral replication in vivo when administered prophylactically. The efficacy of MAb 201 in the treatment of SARS was evaluated in golden Syrian hamsters, an animal model that supports SARS-CoV replication to high levels and displays severe pathological changes associated with infection, including pneumonitis and pulmonary consolidation. METHODS: Golden Syrian hamsters that were intranasally inoculated with SARS-CoV were treated with various doses of MAb 201 or an irrelevant MAb 24 h after inoculation. Two to 7 days after infection, the hamsters were killed, and their lungs were collected for evaluation of viral titers and pathological findings. RESULTS: Postexposure treatment with MAb 201 can alleviate the viral burden and associated pathological findings in a golden Syrian hamster model of SARS-CoV infection. After a hamster is treated with MAb 201, its viral burden is reduced by 102.4-103.9 50% tissue-culture infectious doses per gram of tissue, and the severity of associated pathological findings, including interstitial pneumonitis and consolidation, is also remarkably reduced. CONCLUSIONS: The demonstration of successful postexposure MAb 201 therapy in an animal model that demonstrates viral replication and associated pulmonary pathological findings suggests that MAb 201 may be useful in the arsenal of tools to combat SARS.

Peripheral B cells latently infected with Epstein-Barr virus display molecular hallmarks of classical antigen-selected memory B cells.

Epstein-Barr virus (EBV) establishes a lifelong persistent infection within peripheral blood B cells with the surface phenotype of memory cells. To date there is no proof that these cells have the genotype of true germinal-center-derived memory B cells. It is critical to understand the relative contribution of viral mimicry versus antigen signaling to the production of these cells because EBV encodes proteins that can affect the surface phenotype of infected cells and provide both T cell help and B cell receptor signals in the absence of cognate antigen. To address these questions we have developed a technique to identify single EBV-infected cells in the peripheral blood and examine their expressed Ig genes. The genes were all isotype-switched and somatically mutated. Furthermore, the mutations do not cause stop codons and display the pattern expected for antigen-selected memory cells based on their frequency, type, and location within the Ig gene. We conclude that latently infected peripheral blood B cells display the molecular hallmarks of classical antigen-selected memory B cells. Therefore, EBV does not disrupt the normal processing of latently infected cells into memory, and deviations from normal B cell biology are not tolerated in the infected cells. This article provides definitive evidence that EBV in the peripheral blood persists in true memory B cells.

Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis.

The marked proliferation of activated CD8+ T cells is pathognomonic of EBV-associated infectious mononucleosis (IM), common in young adults. Since the diversity and size of the memory CD8+ T cell population increase with age, we questioned whether IM was mediated by the reactivation of memory CD8+ T cells specific to previously encountered pathogens but cross-reactive with EBV. Of 8 HLA-A2+ IM patients, 5 had activated T cells specific to another common virus, as evidenced by a significantly higher number of peripheral blood influenza A virus M1(58-66)-specific T cells compared with healthy immune donors. Two patients with an augmented M1 response had tetramer-defined cross-reactive cells recognizing influenza M1 and EBV-BMLF1(280-288), which accounted for up to one-third of their BMLF1-specific population and likely contributed to a skewed M1-specific T cell receptor repertoire. These epitopes, with only 33% sequence similarity, mediated differential effects on the function of the cross-reactive T cells, which may contribute to alterations in disease outcome. EBV could potentially encode an extensive pool of T cell epitopes that activate other cross-reactive memory T cells. Our results support the concept that cross-reactive memory CD8+ T cells activated by EBV contribute to the characteristic lymphoproliferation of IM.