CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals
A vital defect in the immune systems of HIV-infected individuals is the loss of CD4⁺ T cells, resulting in impaired immune responses. We hypothesized that there were CD4⁺ T cell–dependent and CD4⁺ T cell–independent alterations in the immune responses of HIV-1⁺ individuals. To test this, we analyzed...
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108235 https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0003-1570-9445 |
| _version_ | 1826193525258059776 |
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| author | Lauffenburger, Douglas A Szeto, Gregory Alter, Galit Irvine, Darrell J Arnold, Kelly B. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Lauffenburger, Douglas A Szeto, Gregory Alter, Galit Irvine, Darrell J Arnold, Kelly B. |
| author_sort | Lauffenburger, Douglas A |
| collection | MIT |
| description | A vital defect in the immune systems of HIV-infected individuals is the loss of CD4⁺ T cells, resulting in impaired immune responses. We hypothesized that there were CD4⁺ T cell–dependent and CD4⁺ T cell–independent alterations in the immune responses of HIV-1⁺ individuals. To test this, we analyzed the secretion of cytokines and chemokines from stimulated peripheral blood mononuclear cell (PBMC) populations from HIV+ donors, healthy donors, and healthy donors with CD4⁺ T cells experimentally depleted. Multivariate analyses of 16 cytokines and chemokines at 6 and 72 hours after three stimuli (antibody-coated beads to stimulate T cells and R848 or lipopolysaccharide to stimulate innate immune cells) enabled integrative analysis of secreted profiles. Two major effects in HIV⁺ PBMCs were not reproduced upon depletion of CD4⁺ T cells in healthy PBMCs: (i) HIV⁺ PBMCs maintained T cell–associated secreted profiles after T cell stimulation; (ii) HIV⁺ PBMCs showed impaired interferon-γ (IFN-γ) secretion early after innate stimulation. These changes arose from hyperactive T cells and debilitated natural killer (NK) cell, respectively. Modeling and experiments showed that early IFN-γ secretion predicted later differences in secreted profiles in vitro. This effect was recapitulated in healthy PBMCs by blocking the IFN-γ receptor. Thus, we identified a critical deficiency in NK cell responses of HIV-infected individuals, independent of CD4⁺ T cell depletion, which directs secreted profiles. Our findings illustrate a broad approach for identifying key disease-associated nodes in a multicellular, multivariate signaling network. |
| first_indexed | 2024-09-23T09:40:49Z |
| format | Article |
| id | mit-1721.1/108235 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:40:49Z |
| publishDate | 2017 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1082352022-09-26T13:03:23Z CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals Lauffenburger, Douglas A Szeto, Gregory Alter, Galit Irvine, Darrell J Arnold, Kelly B. Massachusetts Institute of Technology. Department of Biological Engineering Ragon Institute of MGH, MIT and Harvard Koch Institute for Integrative Cancer Research at MIT Lauffenburger, Douglas A Arnold, Kelly Benedict Szeto, Gregory Alter, Galit Irvine, Darrell J A vital defect in the immune systems of HIV-infected individuals is the loss of CD4⁺ T cells, resulting in impaired immune responses. We hypothesized that there were CD4⁺ T cell–dependent and CD4⁺ T cell–independent alterations in the immune responses of HIV-1⁺ individuals. To test this, we analyzed the secretion of cytokines and chemokines from stimulated peripheral blood mononuclear cell (PBMC) populations from HIV+ donors, healthy donors, and healthy donors with CD4⁺ T cells experimentally depleted. Multivariate analyses of 16 cytokines and chemokines at 6 and 72 hours after three stimuli (antibody-coated beads to stimulate T cells and R848 or lipopolysaccharide to stimulate innate immune cells) enabled integrative analysis of secreted profiles. Two major effects in HIV⁺ PBMCs were not reproduced upon depletion of CD4⁺ T cells in healthy PBMCs: (i) HIV⁺ PBMCs maintained T cell–associated secreted profiles after T cell stimulation; (ii) HIV⁺ PBMCs showed impaired interferon-γ (IFN-γ) secretion early after innate stimulation. These changes arose from hyperactive T cells and debilitated natural killer (NK) cell, respectively. Modeling and experiments showed that early IFN-γ secretion predicted later differences in secreted profiles in vitro. This effect was recapitulated in healthy PBMCs by blocking the IFN-γ receptor. Thus, we identified a critical deficiency in NK cell responses of HIV-infected individuals, independent of CD4⁺ T cell depletion, which directs secreted profiles. Our findings illustrate a broad approach for identifying key disease-associated nodes in a multicellular, multivariate signaling network. Ragon Institute of MGH, MIT and Harvard National Institutes of Health (U.S.) (AI6922694) National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award #F32-CA180586) National Institutes of Health (U.S.) (U19-AI6922694) National Cancer Institute (U.S.) (David H. Koch Center for Integrative Cancer Research. Support (Core) Grant P30-CA14051) 2017-04-18T20:46:22Z 2017-04-18T20:46:22Z 2015-10 2015-10 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/108235 Arnold, K. B., G. L. Szeto, G. Alter, D. J. Irvine, and D. A. Lauffenburger. “CD4+ T Cell-Dependent and CD4+ T Cell-Independent Cytokine-Chemokine Network Changes in the Immune Responses of HIV-Infected Individuals.” Science Signaling 8, no. 399 (October 20, 2015): ra104–ra104. https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0003-1570-9445 en_US http://dx.doi.org/10.1126/scisignal.aab0808 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Lauffenburger, Douglas A Szeto, Gregory Alter, Galit Irvine, Darrell J Arnold, Kelly B. CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals |
| title | CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals |
| title_full | CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals |
| title_fullStr | CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals |
| title_full_unstemmed | CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals |
| title_short | CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals |
| title_sort | cd4 t cell dependent and cd4 t cell independent cytokine chemokine network changes in the immune responses of hiv infected individuals |
| url | http://hdl.handle.net/1721.1/108235 https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0003-1570-9445 |
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