RESUMEN
BACKGROUND: IgE to galactose-alpha-1,3-galactose (alpha-gal) is linked to tick bites and an important cause of anaphylaxis and urticarial reactions to mammalian meat. The alpha-gal syndrome (AGS) is recognized as being common in the southeastern United States. However, prevalence studies are lacking and open questions remain about risk factors and clinical presentation of alpha-gal sensitization. OBJECTIVE: Here we characterized the prevalence as well as the presentation and risk factors of AGS and alpha-gal IgE sensitization in adults in central Virginia recruited without regard to the history of allergic disease. METHODS: Adults in central Virginia, primarily University of Virginia Health employees, were recruited as part of a COVID-19 vaccine study. Subjects provided at least one blood sample and answered questionnaires about medical and dietary history. We used ImmunoCAP for IgE assays and assessed the ABO blood group by reverse typing using stored serum. We also investigated biobanked serum from COVID-19 patients. RESULTS: Median age of the 267 enrollees was 42 years, 76% were female, and 43 (16%) were sensitized to alpha-gal (cutoff of 0.1 IU/mL), of which mammalian meat allergy was reported by seven (2.6%). Sensitized subjects (1) were older, (2) had higher total IgE levels but a similar frequency of IgE to common respiratory allergens, and (3) were more likely to report tick bites than were nonsensitized subjects. Among those who were sensitized, alpha-gal IgE levels were higher among meat-allergic than nonallergic subjects (geometric mean, 9.0 vs 0.5 IU/mL; P < .001). Mammalian meat and dairy consumption was common in individuals with low-level sensitization. CONCLUSION: In central Virginia, AGS is a dominant cause of adult food allergy with a prevalence approaching or exceeding 2%.
RESUMEN
The variable etiology of persistent breathlessness after COVID-19 have confounded efforts to decipher the immunopathology of lung sequelae. Here, we analyzed hundreds of cellular and molecular features in the context of discrete pulmonary phenotypes to define the systemic immune landscape of post-COVID lung disease. Cluster analysis of lung physiology measures highlighted two phenotypes of restrictive lung disease that differed by their impaired diffusion and severity of fibrosis. Machine learning revealed marked CCR5+CD95+ CD8+ T-cell perturbations in mild-to-moderate lung disease, but attenuated T-cell responses hallmarked by elevated CXCL13 in more severe disease. Distinct sets of cells, mediators, and autoantibodies distinguished each restrictive phenotype, and differed from those of patients without significant lung involvement. These differences were reflected in divergent T-cell-based type 1 networks according to severity of lung disease. Our findings, which provide an immunological basis for active lung injury versus advanced disease after COVID-19, might offer new targets for treatment.
RESUMEN
The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1ß, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1ß after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
RESUMEN
The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1ß, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1ß after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
RESUMEN
Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4+ T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1ß, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.
Asunto(s)
Esquistosomiasis mansoni , Animales , Esquistosomiasis mansoni/epidemiología , Antígenos Helmínticos , Schistosoma mansoni , Citocinas , Vacunación , InmunidadRESUMEN
The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of Schistosoma mansoni infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multiple Schistosoma -related immune associations that could explain abrogated vaccine responses in communities with endemic infections. Author Summary: Schistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of Schistosoma mansoni ( S. mansoni ) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.
RESUMEN
Three COVID-19 vaccines have received FDA-authorization and are in use in the United States, but there is limited head-to-head data on the durability of the immune response elicited by these vaccines. Using a quantitative assay we studied binding IgG antibodies elicited by BNT162b2, mRNA-1273 or Ad26.COV2.S in an employee cohort over a span out to 10 months. Age and sex were explored as response modifiers. Of 234 subjects in the vaccine cohort, 114 received BNT162b2, 114 received mRNA-1273 and six received Ad26.COV2.S. IgG levels measured between seven to 20 days after the second vaccination were similar in recipients of BNT162b2 and mRNA-127 and were ~50-fold higher than in recipients of Ad26.COV2.S. However, by day 21 and at later time points IgG levels elicited by BNT162b2 were lower than mRNA-1273. Accordingly, the IgG decay curve was steeper for BNT162b2 than mRNA-1273. Age was a significant modifier of IgG levels in recipients of BNT162b2, but not mRNA-1273. After six months, IgG levels elicited by BNT162b2, but not mRNA-1273, were lower than IgG levels in patients who had been hospitalized with COVID-19 six months earlier. Similar findings were observed when comparing vaccine-elicited antibodies with steady-state IgG targeting seasonal human coronaviruses. Differential IgG decay could contribute to differences observed in clinical protection over time between BNT162b2 and mRNA-1273.
Asunto(s)
Vacuna BNT162 , COVID-19 , Vacuna nCoV-2019 mRNA-1273 , Ad26COVS1 , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Inmunoglobulina G , SARS-CoV-2 , Estados Unidos , VacunaciónRESUMEN
BACKGROUND: Innate lymphoid cells (ILC) are lymphoid lineage innate immune cells that do not mount antigen-specific responses due to their lack of B and T-cell receptors. ILCs are predominantly found at mucosal surfaces, as gatekeepers against invading infectious agents through rapid secretion of immune regulatory cytokines. HIV associated destruction of mucosal lymphoid tissue depletes ILCs, among other immune dysfunctions. Studies have described limited restoration of ILCs during the first three years of combined antiretroviral therapy (cART). Little is known about restoration of ILCs during long-term cART, particularly in sub-Saharan Africa which hosts increasing numbers of adults with at least a decade of cART. RESULTS: We examined phenotypes and function of ILCs from peripheral blood mononuclear cells after 12 years of suppressive cART. We report that ILC1 frequencies (T-BET + CD127 + and CD161 +) were higher in cART-treated HIV-infected relative to age-matched health HIV-negative adults; P = 0.04 whereas ILC precursors (ILCP) were comparable in the two groups (P = 0.56). Interferon gamma (IFN-γ) secretion by ILC1 was higher among cART-treated HIV-infected relative to HIV-negative adults (P = 0.03). CONCLUSION: HIV associated alteration of ILC persisted during cART and may likely affect the quality of host innate and adaptive immune responses during long-term cART.
Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/inmunología , VIH-1/fisiología , Linfocitos/inmunología , Adulto , Estudios de Cohortes , Femenino , Humanos , Inmunidad Innata , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Dominio T Box/genética , Factores de Tiempo , UgandaRESUMEN
BACKGROUND: Detailed understanding of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of coronavirus disease 2019 (CO-VID-19) has been hampered by a lack of quantitative antibody assays. OBJECTIVE: The objective was to develop a quantitative assay for IgG to SARS-CoV-2 proteins that could be implemented in clinical and research laboratories. METHODS: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding domain (RBD) or nucleocapsid protein to the solid phase of the ImmunoCAP. Plasma and serum samples from patients hospitalized with COVID-19 (n = 60) and samples from donors banked before the emergence of COVID-19 (n = 109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform. RESULTS: At a cutoff of 2.5 µg/mL, the assay demonstrated sensitivity and specificity exceeding 95% for IgG to both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 µg/mL (IQR 18-52) and 24.5 µg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples, there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 µg/mL, or 1% of total IgG. CONCLUSIONS: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to mutated COVID-19 proteins, has good performance characteristics, and has a readout in standardized units.
Asunto(s)
Anticuerpos Antivirales/sangre , Prueba Serológica para COVID-19/métodos , COVID-19/diagnóstico , COVID-19/inmunología , Inmunoglobulina G/sangre , SARS-CoV-2/inmunología , Biomarcadores/sangre , COVID-19/virología , Humanos , Estudios Longitudinales , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Detailed understanding of the immune response to SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), has been hampered by a lack of quantitative antibody assays. OBJECTIVE: To develop a quantitative assay for IgG to SARS-CoV-2 proteins that could readily be implemented in clinical and research laboratories. METHODS: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding-domain (RBD) or nucleocapsid protein to the solid-phase of the ImmunoCAP resin. Plasma and serum samples from patients with COVID-19 (n=51) and samples from donors banked prior to the emergence of COVID-19 (n=109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform. RESULTS: Performance characteristics demonstrated 100% sensitivity and 99% specificity at a cut-off level of 2.5 µg/mL for both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 µg/mL (IQR 18-52) and 24.5 µg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 µg/mL, or 1% of total IgG. CONCLUSIONS: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to novel antigens, has good performance characteristics and a read-out in standardized units.
RESUMEN
BACKGROUND: Monocyte dysfunction may persist during antiretroviral therapy (ART). METHODS: Frozen peripheral blood mononuclear cells of 30 human immunodeficiency virus (HIV)-infected ART-treated adults with sustained viral suppression and CD4 counts ≥500 cells/µL were consecutively analyzed for monocyte phenotypes and function. RESULTS: Nonclassical monocytes (CD14+, CD16++), interleukin (IL)-1ß production, and expression of CD40 and CD86 were lower among ART-treated HIV-infected adults relative to age-matched HIV-negative adults (P = .01, P = .01, and P = .02, respectively). Intestinal fatty acid-binding protein, IL6, and soluble CD14 were higher among HIV-infected adults relative to HIV-negative adults (P = .0002, P = .04, and P = .0017, respectively). CONCLUSIONS: Further investigation is required to understand drivers of persistent monocyte activation and dysfunction.
Asunto(s)
Antirretrovirales/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Inflamación/patología , Monocitos/inmunología , Respuesta Virológica Sostenida , Adolescente , Adulto , África , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Estudios Transversales , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Monocitos/química , Adulto JovenRESUMEN
BACKGROUND: We examined NK cell phenotypes and functions after seven years of ART and undetectable viral loads (<50â¯copies/ml) with restored CD4 T-cell counts (≥500â¯cells/µl) and age-matched healthy-HIV-uninfected individuals from the same community. METHODS: Using flow-cytometry, NK cell phenotypes were described using lineage markers (CD56+/-CD16+/-). NK cell activation was determined by expression of activation receptors (NKG2D, NKp44 and NKp46) and activation marker CD69. NK cell function was determined by CD107a, granzyme-b, and IFN-gamma production. RESULTS: CD56 dim and CD56 bright NK cells were lower among ART-treated-HIV-infected than among age-matched-HIV-negative individuals; pâ¯=â¯0.0016 and pâ¯=â¯0.05 respectively. Production of CD107a (Pâ¯=â¯0.004) and Granzyme-B (Pâ¯=â¯0.005) was lower among ART-treated-HIV-infected relative to the healthy-HIV-uninfected individuals. NKG2D and NKp46 were lower, while CD69 expression was higher among ART-treated-HIV-infected than healthy-HIV-uninfected individuals. CONCLUSION: NK cell activation and dysfunction persisted despite seven years of suppressive ART with "normalization" of peripheral CD4 counts.
Asunto(s)
Antirretrovirales/efectos adversos , Infecciones por VIH/inmunología , Células Asesinas Naturales/efectos de los fármacos , Adulto , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Población Negra , Femenino , Granzimas/inmunología , Infecciones por VIH/tratamiento farmacológico , Humanos , Células Asesinas Naturales/inmunología , Lectinas Tipo C/inmunología , Activación de Linfocitos/efectos de los fármacos , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Masculino , Persona de Mediana Edad , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/inmunología , FenotipoRESUMEN
Over the last three decades, a myriad of data has been generated regarding HIV/SIV evolution, immune evasion, immune response, and pathogenesis. Much of this data can be integrated and potentially used to generate a successful vaccine. Although individual approaches have begun to shed light on mechanisms involved in vaccine-conferred protection from infection, true correlates of protection have not yet been identified. The systems biology approach helps unify datasets generated using different techniques and broaden our understanding of HIV immunopathogenesis. Moreover, systems biology is a tool that can provide correlates of protection, which can be targeted for the production of a successful HIV vaccine.
Asunto(s)
Vacunas contra el SIDA/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Biología de Sistemas , Animales , Infecciones por VIH/virología , VIH-1/patogenicidad , HumanosRESUMEN
BACKGROUND: Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. METHODS: We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. RESULTS: We showed that YF-17D-induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D-neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. CONCLUSION: Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. TRIAL REGISTRATION: Registration is not required for observational studies. FUNDING: This study was funded by Canada's Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development.
Asunto(s)
Vacuna contra la Fiebre Amarilla/inmunología , Fiebre Amarilla/inmunología , Fiebre Amarilla/prevención & control , Inmunidad Adaptativa , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Femenino , Humanos , Inmunidad Celular , Inmunidad Humoral , Inmunidad Innata , Inmunización Secundaria , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Suiza , Uganda , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Replicación Viral/inmunología , Fiebre Amarilla/virología , Vacuna contra la Fiebre Amarilla/administración & dosificación , Virus de la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/fisiología , Adulto JovenRESUMEN
Numerous challenges have been identified in vaccine development, including variable efficacy as a function of population demographics and a lack of characterization and mechanistic understanding of immune correlates of protection able to guide delivery and dosing. There is tremendous opportunity in recent technological and computational advances to elucidate systems level understanding of pathogen-host interactions and correlates of immunity. A systems biology approach to vaccinology provides a new paradigm for rational vaccine design in a 'precision medicine' context.
Asunto(s)
Diseño de Fármacos , Vacunas/inmunología , Interacciones Huésped-Patógeno , Humanos , Modelos InmunológicosRESUMEN
Persistent exposure to cognate Ag leads to the functional impairment and exhaustion of HIV-specific CD8 T cells. Ag withdrawal, attributable either to antiretroviral treatment or the emergence of epitope escape mutations, causes HIV-specific CD8 T cell responses to wane over time. However, this process does not continue to extinction, and residual CD8 T cells likely play an important role in the control of HIV replication. In this study, we conducted a longitudinal analysis of clonality, phenotype, and function to define the characteristics of HIV-specific CD8 T cell populations that persist under conditions of limited antigenic stimulation. Ag decay was associated with dynamic changes in the TCR repertoire, increased expression of CD45RA and CD127, decreased expression of programmed death-1, and the emergence of polyfunctional HIV-specific CD8 T cells. High-definition analysis of individual clonotypes revealed that the Ag loss-induced gain of function within HIV-specific CD8 T cell populations could be attributed to two nonexclusive mechanisms: 1) functional improvement of persisting clonotypes; and 2) recruitment of particular clonotypes endowed with superior functional capabilities.
Asunto(s)
Antígenos Virales/inmunología , Linfocitos T CD8-positivos/virología , VIH/inmunología , Linfocitos T CD8-positivos/inmunología , Células Clonales , Regulación de la Expresión Génica/inmunología , Humanos , Subunidad alfa del Receptor de Interleucina-7 , Antígenos Comunes de Leucocito , Estudios Longitudinales , Receptor de Muerte Celular Programada 1RESUMEN
PURPOSE OF REVIEW: Following the evidence that T-cell responses are crucial in the control of HIV-1 infection, vaccines targeting T-cell responses were tested in recent clinical trials. However, these vaccines showed a lack of efficacy. This review attempts to define the qualitative and quantitative features that are desirable for T-cell-induced responses by vaccines. We also describe strategies that could lead to achievement of this goal. RECENT FINDINGS: Using the yellow fever vaccine as a benchmark of an efficient vaccine, recent studies identified factors of immune protection and more importantly innate immune pathways needed for the establishment of long-term protective adaptive immunity. SUMMARY: To prevent or control HIV-1 infection, a vaccine must induce efficient and persistent antigen-specific T cells endowed with mucosal homing capacity. Such cells should have the capability to counteract HIV-1 diversity and its rapid spread from the initial site of infection. To achieve this goal, the activation of a diversified innate immune response is critical. New systems biology approaches will provide more precise correlates of immune protection that will pave the way for new approaches in T-cell-based vaccines.
Asunto(s)
Vacunas contra el SIDA/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Linfocitos T/inmunología , VIH-1/genética , Humanos , Biología de Sistemas/métodosRESUMEN
BACKGROUND: The efficient expansion in vitro of cytolytic CD8+ T cells (CTLs) specific for autologous tumors is crucial both for basic and translational aspects of tumor immunology. We investigated strategies to generate CTLs specific for autologous Non-Small Cell Lung Carcinoma (NSCLC), the most frequent tumor in mankind, using circulating lymphocytes. PRINCIPAL FINDINGS: Classic Mixed Lymphocyte Tumor Cultures with NSCLC cells consistently failed to induce tumor-specific CTLs. Cross-presentation in vitro of irradiated NSCLC cells by autologous dendritic cells, by contrast, induced specific CTL lines from which we obtained a high number of tumor-specific T cell clones (TCCs). The TCCs displayed a limited TCR diversity, suggesting an origin from few tumor-specific T cell precursors, while their TCR molecular fingerprints were detected in the patient's tumor infiltrating lymphocytes, implying a role in the spontaneous anti-tumor response. Grafting NSCLC-specific TCR into primary allogeneic T cells by lentiviral vectors expressing human V-mouse C chimeric TCRalpha/beta chains overcame the growth limits of these TCCs. The resulting, rapidly expanding CD4+ and CD8+ T cell lines stably expressed the grafted chimeric TCR and specifically recognized the original NSCLC. CONCLUSIONS: This study defines a strategy to efficiently induce and propagate in vitro T cells specific for NSCLC starting from autologous peripheral blood lymphocytes.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Animales , Presentación de Antígeno , Linfocitos T CD8-positivos/citología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Células Clonales , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Trasplante HomólogoRESUMEN
Evaluation of: Martin-Orozco N, Muranski P, Chung Y et al.: T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31(5), 787-798 (2009). The immune system plays an important role in tumor control. Tumor antigen-specific CD4(+) and CD8(+) T cells are being actively exploited in cancer immunotherapy protocols that often attain clinical responses. The T helper (Th)1 effector cytokine profile, epitomized by the production of IFN-gamma, is considered the optimal pathway in controlling tumor growth. In this study, Martin-Orozco challenges this notion by demonstrating that newly defined Th17 effector T cells display a stronger anti-tumor effect vis a vis with Th1 cells. Th17 cells produce the strongly inflammatory cytokines IL-17A and IL-17F, and so far have been implicated in the response to infectious pathogens and in autoimmunity. This study reveals that Th17 cells protect against cancer, not only by triggering a potent nonantigen-specific intratumor inflammatory infiltrate, but also, and remarkably, by providing a more significant help than Th1 cells for the efficient induction, expansion, differentiation and tumor homing of tumor-specific CD8(+) T cells. This study, therefore, sheds new light on the effector functions of Th17 cells and has strong implications for their translation into clinical applications for cancer immunotherapy.