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Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.
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Inmunidad Adaptativa/inmunología , Envejecimiento/inmunología , Sistema Inmunológico/inmunología , Inmunidad Innata/inmunología , Animales , Senescencia Celular/inmunología , Humanos , Linfocitos/inmunología , Linfocitos/metabolismo , Modelos Inmunológicos , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
In the version of this article initially published, the year of birth provided (1960) was incorrect. The correct year is 1961. The error has been corrected in the HTML and PDF versions of the article.
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In the version of this Review initially published, the type of cell in the final sentence of the legend to Figure 3 (group 2 innate lymphoid cells) was incorrect. The correct type of cell is group 3 innate lymphoid cells. The error has been corrected in the HTML and PDF versions of the article.
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Memory B cells (MBCs) can respond to heterologous antigens either by molding new specificities through secondary germinal centers (GCs) or by selecting preexisting clones without further affinity maturation. To distinguish these mechanisms in flavivirus infections and immunizations, we studied recall responses to envelope protein domain III (DIII). Conditional deletion of activation-induced cytidine deaminase (AID) between heterologous challenges of West Nile, Japanese encephalitis, Zika, and dengue viruses did not affect recall responses. DIII-specific MBCs were contained mostly within the plasma-cell-biased CD80+ subset, and few GCs arose following heterologous boosters, demonstrating that recall responses are confined by preexisting clonal diversity. Measurement of monoclonal antibody (mAb) binding affinity to DIII proteins, timed AID deletion, single-cell RNA sequencing, and lineage tracing experiments point to selection of relatively low-affinity MBCs as a mechanism to promote diversity. Engineering immunogens to avoid this MBC diversity may facilitate flavivirus-type-specific vaccines with minimized potential for infection enhancement.
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Linfocitos B/inmunología , Reacciones Cruzadas/inmunología , Infecciones por Flavivirus/inmunología , Infecciones por Flavivirus/virología , Flavivirus/inmunología , Interacciones Huésped-Patógeno/inmunología , Memoria Inmunológica , Animales , Linfocitos B/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta Inmunológica , Infecciones por Flavivirus/metabolismo , Inmunización , Ratones , Ratones Noqueados , Ratones Transgénicos , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Especificidad de la EspecieRESUMEN
We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
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Betacoronavirus/inmunología , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Inmunidad Humoral , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Arizona/epidemiología , Betacoronavirus/aislamiento & purificación , COVID-19 , Prueba de COVID-19 , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Proteínas de la Nucleocápside de Coronavirus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de la Nucleocápside/inmunología , Pandemias , Fosfoproteínas , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Prevalencia , Dominios y Motivos de Interacción de Proteínas , SARS-CoV-2 , Estudios Seroepidemiológicos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto JovenRESUMEN
The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.
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Envejecimiento/inmunología , Linfocitos T CD8-positivos/fisiología , Memoria Inmunológica , Inmunosenescencia , Subgrupos de Linfocitos T/fisiología , Virosis/inmunología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Humanos , Inmunofenotipificación , Activación de Linfocitos , Persona de Mediana Edad , Fenotipo , Transcriptoma , Adulto JovenRESUMEN
Secondary lymphoid organs (SLOs) (including the spleen and lymph nodes [LNs]) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used "time stamping" to indelibly mark newly generated naive T cells (also known as recent thymic emigrants) (RTEs) in mice, and followed their presence, phenotype, and retention in SLOs. We found that SLOs involute asynchronously. Skin-draining LNs atrophied by 6 to 9 mo in life, whereas deeper tissue-draining LNs atrophied by 18 to 20 mo, as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTEs at all ages entered SLOs and successfully completed postthymic differentiation, but the capacity of older SLOs to maintain TN numbers was reduced with aging, and that trait did not depend on the age of TNs. However, in SLOs of older mice, these cells exhibited an emigration phenotype (CCR7loS1P1hi), which correlated with an increase of the cells of the same phenotype in the blood. Finally, upon intradermal immunization, RTEs generated in mice barely participated in de novo immune responses and failed to produce well-armed effector cells detectable in blood as early as by 7 to 8 mo of age. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated reduction of cutaneous immunity with aging.
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Ganglios Linfáticos , Piel , Envejecimiento , Animales , Atrofia/patología , Ratones , Ratones Endogámicos C57BL , Piel/patologíaRESUMEN
Lassa virus (LASV) is the causative agent of Lassa fever (LF), which presents as a lethal hemorrhagic disease in severe cases. LASV-induced hearing loss in survivors is a huge socioeconomic burden, however, the mechanism(s) leading to hearing loss is unknown. In this study, we evaluate in a mouse LF model the auditory function using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to determine the mechanisms underlying LASV-induced hearing loss. In the process, we pioneered measures of ABR and DPOAE tests in rodents in biosafety level 4 (BSL-4) facilities. Our T cell depletion studies demonstrated that CD4 T-cells play an important role in LASV-induced hearing loss, while CD8 T-cells are critical for the pathogenicity in the acute phase of LASV infection. Results presented in this study may help to develop future countermeasures against acute disease and LASV-induced hearing loss.
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Pérdida Auditiva , Fiebre de Lassa , Animales , Linfocitos T CD4-Positivos , Modelos Animales de Enfermedad , Virus Lassa , RatonesAsunto(s)
Alergia e Inmunología/historia , Animales , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Several studies have demonstrated that the SARS-CoV-2 variant-of-concern B.1.1.529 (Omicron) exhibits a high degree of escape from Ab neutralization. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron. To this purpose, we analyzed a human cohort (n = 327 subjects) of two- or three-dose mRNA vaccine recipients and COVID-19 postinfection subjects. We report that T cell responses against Omicron were largely preserved. IFN-γ-producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (â¼20%) loss in IL-2 single or IL-2+IFN-γ+ polyfunctional responses. Three-dose vaccinated participants had similar responses to Omicron relative to post-COVID-19 participants and exhibited responses significantly higher than those receiving two mRNA vaccine doses. These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.
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Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Linfocitos T , Vacunas de ARNm , Anticuerpos Antivirales , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Humanos , Inmunidad Celular , Interleucina-2/genética , Linfocitos T/inmunología , Vacunación , Vacunas Sintéticas , Vacunas de ARNm/inmunologíaRESUMEN
BACKGROUND: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) on host cells. Multiple cells and organs are targeted, particularly airway epithelial cells. OM-85, a standardized lysate of human airway bacteria with strong immunomodulating properties and an impeccable safety profile, is widely used to prevent recurrent respiratory infections. We found that airway OM-85 administration inhibits Ace2 and Tmprss2 transcription in the mouse lung, suggesting that OM-85 might hinder SARS-CoV-2/host cell interactions. OBJECTIVES: We sought to investigate whether and how OM-85 treatment protects nonhuman primate and human epithelial cells against SARS-CoV-2. METHODS: ACE2 and TMPRSS2 mRNA and protein expression, cell binding of SARS-CoV-2 S1 protein, cell entry of SARS-CoV-2 S protein-pseudotyped lentiviral particles, and SARS-CoV-2 cell infection were measured in kidney, lung, and intestinal epithelial cell lines, primary human bronchial epithelial cells, and ACE2-transfected HEK293T cells treated with OM-85 in vitro. RESULTS: OM-85 significantly downregulated ACE2 and TMPRSS2 transcription and surface ACE2 protein expression in epithelial cell lines and primary bronchial epithelial cells. OM-85 also strongly inhibited SARS-CoV-2 S1 protein binding to, SARS-CoV-2 S protein-pseudotyped lentivirus entry into, and SARS-CoV-2 infection of epithelial cells. These effects of OM-85 appeared to depend on SARS-CoV-2 receptor downregulation. CONCLUSIONS: OM-85 inhibits SARS-CoV-2 epithelial cell infection in vitro by downregulating SARS-CoV-2 receptor expression. Further studies are warranted to assess whether OM-85 may prevent and/or reduce the severity of coronavirus disease 2019.
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Adyuvantes Inmunológicos/administración & dosificación , COVID-19/prevención & control , Extractos Celulares/administración & dosificación , Receptores Virales/antagonistas & inhibidores , Receptores Virales/inmunología , SARS-CoV-2/inmunología , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/inmunología , Animales , COVID-19/inmunología , COVID-19/virología , Células CACO-2 , Extractos Celulares/inmunología , Células Cultivadas , Chlorocebus aethiops , Regulación hacia Abajo/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/virología , Células HEK293 , Interacciones Microbiota-Huesped/efectos de los fármacos , Interacciones Microbiota-Huesped/inmunología , Humanos , Técnicas In Vitro , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/virología , Ratones , Ratones Endogámicos BALB C , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Transcripción Genética/efectos de los fármacos , Transcripción Genética/inmunología , Células VeroRESUMEN
BACKGROUND: Data on the development of neutralizing antibodies (nAbs) against SARS-CoV-2 after SARS-CoV-2 infection and after vaccination with mRNA COVID-19 vaccines are limited. METHODS: From a prospective cohort of 3975 adult essential and frontline workers tested weekly from August 2020 to March 2021 for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction assay irrespective of symptoms, 497 participants had sera drawn after infection (170), vaccination (327), and after both infection and vaccination (50 from the infection population). Serum was collected after infection and each vaccine dose. Serum-neutralizing antibody titers against USA-WA1/2020-spike pseudotype virus were determined by the 50% inhibitory dilution. Geometric mean titers (GMTs) and corresponding fold increases were calculated using t tests and linear mixed-effects models. RESULTS: Among 170 unvaccinated participants with SARS-CoV-2 infection, 158 (93%) developed nAbs with a GMT of 1003 (95% confidence interval, 766-1315). Among 139 previously uninfected participants, 138 (99%) developed nAbs after mRNA vaccine dose 2 with a GMT of 3257 (2596-4052). GMT was higher among those receiving mRNA-1273 vaccine (GMT, 4698; 3186-6926) compared with BNT162b2 vaccine (GMT, 2309; 1825-2919). Among 32 participants with prior SARS-CoV-2 infection, GMT was 21â 655 (14 766-31â 756) after mRNA vaccine dose 1, without further increase after dose 2. CONCLUSIONS: A single dose of mRNA vaccine after SARS-CoV-2 infection resulted in the highest observed nAb response. Two doses of mRNA vaccine in previously uninfected participants resulted in higher nAbs to SARS-CoV-2 than after 1 dose of vaccine or SARS-CoV-2 infection alone. nAb response also differed by mRNA vaccine product.
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Vacunas contra la COVID-19 , COVID-19 , Vacuna nCoV-2019 mRNA-1273 , Adulto , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Humanos , Pruebas de Neutralización , Estudios Prospectivos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Premenopausal females are protected from angiotensin II (ANG II)-induced hypertension following the adoptive transfer of T cells from normotensive donors. For the present study, we hypothesized that the transfer of hypertensive T cells (HT) or splenocytes (HS) from hypertensive donors would eliminate premenopausal protection from hypertension. Premenopausal recombination-activating gene-1 (Rag-1)-/- females received either normotensive (NT) or hypertensive cells 3 wk before ANG II infusion (14 days, 490 ng/kg/min). Contrary to our hypothesis, no increase in ANG II-induced blood pressure was observed in the NT/ANG or HT/ANG groups. Flow cytometry demonstrated that renal FoxP3+ T regulatory cells were significantly decreased, and immunohistochemistry showed an increase in renal F4/80+ macrophages in the HT/ANG group, suggesting a shift in the renal inflammatory environment despite no change in blood pressure. Renal mRNA expression of macrophage chemoattractant protein-1 (MCP-1), endothelin-1 (ET-1), and G protein-coupled estrogen receptor-1 (GPER-1) was significantly decreased in the HT/ANG group. The adoptive transfer of hypertensive splenocytes before ANG II infusion (HS/ANG) eliminated premenopausal protection from hypertension and significantly decreased splenic FoxP3+ T regulatory cells compared with females that received normotensive splenocytes (NS/ANG). Expression of macrophage inflammatory protein 1α/chemokine (C-C motif) ligand 3 (MCP-1/CCL3), a potent macrophage chemokine, was elevated in the HS/ANG group; however, no increase in renal macrophage infiltration occurred. Together, these data show that in premenopausal females, T cells from hypertensive donors are not sufficient to induce robust ANG II-mediated hypertension; in contrast, transfer of hypertensive splenocytes (consisting of T/B lymphocytes, dendritic cells, and macrophages) is sufficient. Further work is needed to understand how innate and adaptive immune cells and estrogen signaling coordinate to cause differential hypertensive outcomes in premenopausal females.NEW & NOTEWORTHY Our study is the first to explore the role of hypertensive T cells versus hypertensive splenocytes in premenopausal protection from ANG II-induced hypertension. We show that the hypertensive status of T cell donors does not impact blood pressure in the recipient female. However, splenocytes, when transferred from hypertensive donors, significantly increased premenopausal recipient blood pressure following ANG II infusion, highlighting the importance of further investigation into estrogen signaling and immune cell activation in females.
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Traslado Adoptivo , Presión Arterial , Hipertensión/inmunología , Activación de Linfocitos , Bazo/trasplante , Linfocitos T/trasplante , Factores de Edad , Angiotensina II , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Endotelina-1/genética , Endotelina-1/metabolismo , Femenino , Proteínas de Homeodominio/genética , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Osteopontina/genética , Osteopontina/metabolismo , Premenopausia , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Factores Sexuales , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The scale of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has thrust immunology into the public spotlight in unprecedented ways. In this article, which is part opinion piece and part review, we argue that the normal cadence by which we discuss science with our colleagues failed to properly convey likelihoods of the immune response to SARS-CoV-2 to the public and the media. As a result, biologically implausible outcomes were given equal weight as the principles set by decades of viral immunology. Unsurprisingly, questionable results and alarmist news media articles have filled the void. We suggest an emphasis on setting expectations based on prior findings while avoiding the overused approach of assuming nothing. After reviewing Ab-mediated immunity after coronavirus and other acute viral infections, we posit that, with few exceptions, the development of protective humoral immunity of more than a year is the norm. Immunity to SARS-CoV-2 is likely to follow the same pattern.
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Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Inmunidad Humoral , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Adulto , Anciano , Anticuerpos Neutralizantes/inmunología , Linfocitos B/inmunología , Betacoronavirus/genética , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Humanos , Memoria Inmunológica , Persona de Mediana Edad , Pandemias , Neumonía Viral/virología , Reacción en Cadena de la Polimerasa , SARS-CoV-2 , SeroconversiónRESUMEN
BACKGROUND: Cellular changes in adaptive immune system accompany the process of aging and contribute to an aging-related immune phenotype (ARIP) characterized by decrease in naïve T-cells (TN) and increase in memory T-cells (TM). A population-representative marker of ARIP and its associations with biological aging and age-related chronic conditions have not been studied previously. METHODS: We developed two ARIP indicators based on well understood age-related changes in T cell distribution: TN/(TCM (Central Memory) + TEM (Effector Memory) + TEFF (Effector)) (referred as TN/TM) in CD4 + and CD8 + T-cells. We compared them with existing ARIP measures including CD4/CD8 ratio and CD8 + TN cells by evaluating associations with chronological age and the Klemera Doubal measure of biological age (measured in years) using linear regression, multimorbidity using multinomial logistic regression and two-year mortality using logistic regression. RESULTS: CD8 + TN and CD8 + TN/TM had the strongest inverse association with chronological age (beta estimates: -3.41 and -3.61 respectively; p-value < 0.0001) after adjustment for sex, race/ethnicity and CMV status. CD4 + TN/TM and CD4 + TN had the strongest inverse association with biological age (ß = -0.23; p = 0.003 and ß = -0.24; p = 0.004 respectively) after adjustment for age, sex, race/ethnicity and CMV serostatus. CD4/CD8 ratio was not associated with chronological age or biological age. CD4 + TN/TM and CD4 + TN was inversely associated with multimorbidity. For CD4 + TN/TM, people with 2 chronic conditions had an odds ratio of for 0.74 (95%CI: 0.63-0.86 p = 0.0003) compared to those without any chronic conditions while those with 3 chronic conditions had an odds ratio of 0.75 (95% CI: 0.63-0.90; p = 0.003) after adjustment for age, sex, race/ethnicity, CMV serostatus, smoking, and BMI. The results for the CD4 + TN subset were very similar to the associations seen with the CD4 + TN/TM. CD4 + TN/TM and CD4 + TN were both associated with two-year mortality (OR = 0.80 (95% CI: 0.67-0.95; p = 0.01) and 0.81 (0.70-0.94; p = 0.01), respectively). CONCLUSION: CD4 + TN/TM and CD4 + TN had a stronger association with biological age, age-related morbidity and mortality compared to other ARIP measures. Future longitudinal studies are needed to evaluate the utility of the CD4 + subsets in predicting the risk of aging-related outcomes.
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Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.
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Tejido Adiposo , Linfocitos T CD8-positivos , Infecciones por Herpesviridae , Hiperglucemia , Muromegalovirus/inmunología , Paniculitis , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Tejido Adiposo/virología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/patología , Infecciones por Herpesviridae/virología , Hiperglucemia/genética , Hiperglucemia/inmunología , Hiperglucemia/patología , Hiperglucemia/virología , Memoria Inmunológica , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Ratones , Ratones Noqueados , Paniculitis/genética , Paniculitis/inmunología , Paniculitis/patología , Paniculitis/virologíaRESUMEN
Lifelong interactions between host and the ubiquitous and persistent cytomegalovirus (CMV) have been proposed to contribute to the age-related decline in immunity. Prior work from us and others found some support for that idea, yet evidence that this led to increased vulnerability to other infections was not obtained. Moreover, evidence has accumulated that CMV infection can be beneficial to immune defense in young/adult mice and humans, dominantly via enhanced innate immunity. Here, we describe an unexpected impact of murine CMV (MCMV) upon the T cell response of old mice to Listeria monocytogenes expressing the model antigen, OVA (Lm-OVA). Single-cell sequencing of the OVA-specific CD8 T cell receptor ß (TCRß) repertoire of old mice demonstrated that old MCMV-infected mice recruited many diverse clonotypes that afforded broad and often more efficient recognition of antigenic peptide variants. This stood in contrast to old control mice, which exhibited strong narrowing and homogenization of the elicited repertoire. High-throughput sequencing of the total naïve CD8 TCRß repertoire showed that many of these diverse OVA-specific clonotypes were present in the naïve CD8 repertoire of mice in all groups (adult, old control, and old MCMV+) yet were only recruited into the Lm-OVA response in MCMV+ old mice. These results have profound implications for our understanding of T cell immunity over a life span and suggest that our coevolution with CMV may include surprising, potentially positive impacts on adaptive heterologous immunity in late life.
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Linfocitos T CD8-positivos/inmunología , Infecciones por Citomegalovirus/inmunología , Inmunidad Celular , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Muromegalovirus/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Linfocitos T CD8-positivos/patología , Infecciones por Citomegalovirus/patología , Listeriosis/patología , Masculino , RatonesRESUMEN
The transcriptional program associated with herpesvirus latency and the viral genes regulating entry into and exit from latency are poorly understood and controversial. Here, we developed and validated a targeted enrichment platform and conducted large-scale transcriptome analyses of human cytomegalovirus (HCMV) infection. We used both an experimental hematopoietic cell model of latency and cells from naturally infected, healthy human subjects (clinical) to define the breadth of viral genes expressed. The viral transcriptome derived from experimental infection was highly correlated with that from clinical infection, validating our experimental latency model. These transcriptomes revealed a broader profile of gene expression during infection in hematopoietic cells than previously appreciated. Further, using recombinant viruses that establish a nonreactivating, latent-like or a replicative infection in CD34+ hematopoietic progenitor cells, we defined classes of low to moderately expressed genes that are differentially regulated in latent vs. replicative states of infection. Most of these genes have yet to be studied in depth. By contrast, genes that were highly expressed, were expressed similarly in both latent and replicative infection. From these findings, a model emerges whereby low or moderately expressed genes may have the greatest impact on regulating the switch between viral latency and replication. The core set of viral genes expressed in natural infection and differentially regulated depending on the pattern of infection provides insight into the HCMV transcriptome associated with latency in the host and a resource for investigating virus-host interactions underlying persistence.
Asunto(s)
Citomegalovirus/genética , Regulación Viral de la Expresión Génica , Genoma Viral , Interacciones Huésped-Patógeno , Transcriptoma , Latencia del Virus , Línea Celular , Citomegalovirus/crecimiento & desarrollo , Citomegalovirus/metabolismo , Fibroblastos/virología , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/virología , Humanos , Cultivo Primario de Células , Transducción de Señal , Proteínas Virales/genética , Proteínas Virales/metabolismo , Replicación ViralRESUMEN
Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1-/- mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3+ T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1-/- menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females.NEW & NOTEWORTHY Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.
Asunto(s)
Presión Sanguínea , Factores de Transcripción Forkhead/inmunología , Hipertensión/inmunología , Depleción Linfocítica , Menopausia/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Angiotensina II , Animales , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Frecuencia Cardíaca , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/fisiopatología , Riñón/inmunología , Riñón/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Menopausia/metabolismo , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores Sexuales , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplanteRESUMEN
Aging is accompanied by significant defects in immunity and compromised responses to new, previously unencountered microbial pathogens. Most humans carry several persistent or latent viruses as they age, interacting with the host immune systems for years. In that context maybe the most studied persistent virus is Cytomegalovirus, infamous for its ability to recruit very large T cell responses which increase with age and to simultaneously evade elimination by the immune system. Here we will address how lifelong CMV infection and the immunological burden of its control might affect immune reactivity and health of the host over time.