Cargando…
Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls
Immune cells are, by default, migratory cells that traverse tissue for the purpose of carrying out recognition and recruitment in pathologic inflammation and infection. Members of the LDL receptor family (LDL-RFMs) interact with human leukocyte elastase on the cell surface (HLE-CS) in complex with t...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881272/ https://www.ncbi.nlm.nih.gov/pubmed/31824943 http://dx.doi.org/10.3389/fcell.2019.00278 |
_version_ | 1783473909793816576 |
---|---|
author | Bristow, Cynthia L. Ferrando-Martinez, Sara Ruiz-Mateos, Ezequiel Leal, Manuel Winston, Ronald |
author_facet | Bristow, Cynthia L. Ferrando-Martinez, Sara Ruiz-Mateos, Ezequiel Leal, Manuel Winston, Ronald |
author_sort | Bristow, Cynthia L. |
collection | PubMed |
description | Immune cells are, by default, migratory cells that traverse tissue for the purpose of carrying out recognition and recruitment in pathologic inflammation and infection. Members of the LDL receptor family (LDL-RFMs) interact with human leukocyte elastase on the cell surface (HLE-CS) in complex with the abundant blood protein α1proteinase inhibitor (α1PI, α1-antitrypsin, Alpha-1), a process that induces internalization of aggregated functionally-related receptors, including CD4 and the T cell antigen receptor, while simultaneously promoting cellular locomotion. We sought to determine whether augmenting α1PI blood concentration would promote the locomotion of immature T cells through the thymus and generate new CD4(+) T cells. Two small clinical trials (NCT01370018, NCT01731691, https://clinicaltrials.gov) were conducted in which HIV-1 infected and uninfected individuals were augmented with α1PI and compared with placebo-treated subjects and untreated controls. Blood cell phenotypes were monitored weekly. We found that CD4/CD8 ratio was significantly increased by α1PI augmentation in both uninfected and HIV-1 infected individuals. We found that maturation of CD4(+)CD8(+) T cells to become immunologically competent CD4(+) T cells was regulated by α1PI. We propose a strategy targeting HLE-CS for treating secondary immunodeficiency for which there is currently no direct treatment. Treatment to directly elevate T cells in patients with secondary immunodeficiency, including HIV disease, can be provided by alpha-1 antitrypsin augmentation or small molecules that target HLE-CS. Because individuals infected with HIV-1 produce a monoclonal antibody, 3F5, which binds to and inactivates α1PI, a process that prevents α1PI from binding to HLE-CS, thereby blocking locomotion of immature T cells through the thymus to generate CD4(+) T cells, we further propose that HIV-1 vaccination should include induction of an antibody that binds to and blocks 3F5 activity, thereby preventing AIDS in addition to the current vaccine strategy for preventing HIV-1 infection. |
format | Online Article Text |
id | pubmed-6881272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68812722019-12-10 Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls Bristow, Cynthia L. Ferrando-Martinez, Sara Ruiz-Mateos, Ezequiel Leal, Manuel Winston, Ronald Front Cell Dev Biol Cell and Developmental Biology Immune cells are, by default, migratory cells that traverse tissue for the purpose of carrying out recognition and recruitment in pathologic inflammation and infection. Members of the LDL receptor family (LDL-RFMs) interact with human leukocyte elastase on the cell surface (HLE-CS) in complex with the abundant blood protein α1proteinase inhibitor (α1PI, α1-antitrypsin, Alpha-1), a process that induces internalization of aggregated functionally-related receptors, including CD4 and the T cell antigen receptor, while simultaneously promoting cellular locomotion. We sought to determine whether augmenting α1PI blood concentration would promote the locomotion of immature T cells through the thymus and generate new CD4(+) T cells. Two small clinical trials (NCT01370018, NCT01731691, https://clinicaltrials.gov) were conducted in which HIV-1 infected and uninfected individuals were augmented with α1PI and compared with placebo-treated subjects and untreated controls. Blood cell phenotypes were monitored weekly. We found that CD4/CD8 ratio was significantly increased by α1PI augmentation in both uninfected and HIV-1 infected individuals. We found that maturation of CD4(+)CD8(+) T cells to become immunologically competent CD4(+) T cells was regulated by α1PI. We propose a strategy targeting HLE-CS for treating secondary immunodeficiency for which there is currently no direct treatment. Treatment to directly elevate T cells in patients with secondary immunodeficiency, including HIV disease, can be provided by alpha-1 antitrypsin augmentation or small molecules that target HLE-CS. Because individuals infected with HIV-1 produce a monoclonal antibody, 3F5, which binds to and inactivates α1PI, a process that prevents α1PI from binding to HLE-CS, thereby blocking locomotion of immature T cells through the thymus to generate CD4(+) T cells, we further propose that HIV-1 vaccination should include induction of an antibody that binds to and blocks 3F5 activity, thereby preventing AIDS in addition to the current vaccine strategy for preventing HIV-1 infection. Frontiers Media S.A. 2019-11-21 /pmc/articles/PMC6881272/ /pubmed/31824943 http://dx.doi.org/10.3389/fcell.2019.00278 Text en Copyright © 2019 Bristow, Ferrando-Martinez, Ruiz-Mateos, Leal and Winston. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Bristow, Cynthia L. Ferrando-Martinez, Sara Ruiz-Mateos, Ezequiel Leal, Manuel Winston, Ronald Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls |
title | Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls |
title_full | Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls |
title_fullStr | Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls |
title_full_unstemmed | Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls |
title_short | Development of Immature CD4(+)CD8(+)T Cells Into Mature CD4(+) T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls |
title_sort | development of immature cd4(+)cd8(+)t cells into mature cd4(+) t cells requires alpha-1 antitrypsin as observed by treatment in hiv-1 infected and uninfected controls |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881272/ https://www.ncbi.nlm.nih.gov/pubmed/31824943 http://dx.doi.org/10.3389/fcell.2019.00278 |
work_keys_str_mv | AT bristowcynthial developmentofimmaturecd4cd8tcellsintomaturecd4tcellsrequiresalpha1antitrypsinasobservedbytreatmentinhiv1infectedanduninfectedcontrols AT ferrandomartinezsara developmentofimmaturecd4cd8tcellsintomaturecd4tcellsrequiresalpha1antitrypsinasobservedbytreatmentinhiv1infectedanduninfectedcontrols AT ruizmateosezequiel developmentofimmaturecd4cd8tcellsintomaturecd4tcellsrequiresalpha1antitrypsinasobservedbytreatmentinhiv1infectedanduninfectedcontrols AT lealmanuel developmentofimmaturecd4cd8tcellsintomaturecd4tcellsrequiresalpha1antitrypsinasobservedbytreatmentinhiv1infectedanduninfectedcontrols AT winstonronald developmentofimmaturecd4cd8tcellsintomaturecd4tcellsrequiresalpha1antitrypsinasobservedbytreatmentinhiv1infectedanduninfectedcontrols |