Soluble CD40 ligand contributes to dendritic cell-mediated T-cell dysfunction in HIV-1 infection
Elizabeth A Miller, Ramya Gopal, Vanessa Valdes, Jeffrey S Berger, Nina Bhardwaj, Meagan P O'Brien, Elizabeth A Miller, Ramya Gopal, Vanessa Valdes, Jeffrey S Berger, Nina Bhardwaj, Meagan P O'Brien
Abstract
Objective: Plasma soluble CD40 ligand (sCD40L) is increased during HIV-1 infection, but it is unknown whether it circulates in monomeric or multimeric forms, and whether the circulating forms have differential effects on myeloid dendritic cell function and adaptive regulation.
Design: sCD40L forms were measured in plasma samples from HIV-infected donors. The effects of sCD40L forms on dendritic cell function were measured in vitro.
Methods: To delineate which forms of sCD40L are present in plasma from HIV-infected donors, immunoblots were performed following enrichment of plasma for medium and low-abundance proteins. Dendritic cells from seronegative donors were exposed to multiple forms of sCD40L prior to Toll-like receptor stimulation and dendritic cell function and adaptive regulation was assessed in vitro.
Results: Monomeric and multimeric forms of sCD40L were identified in plasma from antiretroviral therapy-treated HIV-infected donors. Although monomeric and multimeric forms of sCD40L had differential effects on dendritic cell activation when given alone, both strongly suppressed secretion of the Th1 skewing cytokine, interleukin-12, upon subsequent Toll-like receptor stimulation. Furthermore, dendritic cells exposed to both monomeric and multimeric sCD40L induced regulatory T-cell formation and T-cell anergy.
Conclusion: Elevated sCD40L during HIV infection impairs dendritic cell function, contributing to innate and adaptive immune dysfunction. Antiretroviral adjunctive therapies that decrease sCD40L may provide immune modulatory benefits.
Figures
![Figure 1. Soluble CD40L circulates in plasma…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4478195/bin/nihms-678224-f0001.jpg)
Figure 2. DCs incubated with sCD40L monomeric…
Figure 2. DCs incubated with sCD40L monomeric as compared to multimeric forms have differential effects…
Figure 3. DCs exposed to both monomeric…
Figure 3. DCs exposed to both monomeric and multimeric sCD40L induce IDO expression and regulatory…
Figure 4. DCs exposed to both monomeric…
Figure 4. DCs exposed to both monomeric and multimeric sCD40L induce anergy, which is not…
- Soluble CD40-ligand (sCD40L, sCD154) plays an immunosuppressive role via regulatory T cell expansion in HIV infection.Jenabian MA, Patel M, Kema I, Vyboh K, Kanagaratham C, Radzioch D, Thébault P, Lapointe R, Gilmore N, Ancuta P, Tremblay C, Routy JP. Jenabian MA, et al. Clin Exp Immunol. 2014 Oct;178(1):102-11. doi: 10.1111/cei.12396. Clin Exp Immunol. 2014. PMID: 24924152 Free PMC article.
- Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway.Miller EA, Spadaccia MR, OʼBrien MP, Rolnitzky L, Sabado R, Manches O, Frleta D, Bhardwaj N. Miller EA, et al. J Acquir Immune Defic Syndr. 2012 Dec 15;61(5):535-44. doi: 10.1097/QAI.0b013e31826afbce. J Acquir Immune Defic Syndr. 2012. PMID: 22902724 Free PMC article.
- Chronic immune activation in HIV-1 infection contributes to reduced interferon alpha production via enhanced CD40:CD40 ligand interaction.Donhauser N, Pritschet K, Helm M, Harrer T, Schuster P, Ries M, Bischof G, Vollmer J, Smola S, Schmidt B; German Competence Network HIV/AIDS. Donhauser N, et al. PLoS One. 2012;7(3):e33925. doi: 10.1371/journal.pone.0033925. Epub 2012 Mar 21. PLoS One. 2012. PMID: 22470494 Free PMC article.
- Dendritic cells at the interface of innate and adaptive immunity to HIV-1.Smed-Sörensen A, Loré K. Smed-Sörensen A, et al. Curr Opin HIV AIDS. 2011 Sep;6(5):405-10. doi: 10.1097/COH.0b013e328349b06b. Curr Opin HIV AIDS. 2011. PMID: 21743321 Review.
- Dendritic cell dysregulation during HIV-1 infection.Miller E, Bhardwaj N. Miller E, et al. Immunol Rev. 2013 Jul;254(1):170-89. doi: 10.1111/imr.12082. Immunol Rev. 2013. PMID: 23772620 Free PMC article. Review.
- Chronic Alcohol Exposure Among People Living with HIV Is Associated with Innate Immune Activation and Alterations in Monocyte Phenotype and Plasma Cytokine Profile.Underwood ML, Park B, Uebelhoer LS, Gu G, Kunkel LE, Korthuis PT, Cook RR, Sekaly RP, Ribeiro SP, Lancioni CL. Underwood ML, et al. Front Immunol. 2022 Mar 18;13:867937. doi: 10.3389/fimmu.2022.867937. eCollection 2022. Front Immunol. 2022. PMID: 35371104 Free PMC article.
- Dual Antiretroviral Therapy-All Quiet Beneath the Surface?van Welzen BJ, Oomen PGA, Hoepelman AIM. van Welzen BJ, et al. Front Immunol. 2021 Feb 12;12:637910. doi: 10.3389/fimmu.2021.637910. eCollection 2021. Front Immunol. 2021. PMID: 33643320 Free PMC article. Review.
- Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis.Lai JH, Luo SF, Ho LJ. Lai JH, et al. Cells. 2019 Aug 18;8(8):927. doi: 10.3390/cells8080927. Cells. 2019. PMID: 31426619 Free PMC article. Review.
- Poly-ICLC, a TLR3 Agonist, Induces Transient Innate Immune Responses in Patients With Treated HIV-Infection: A Randomized Double-Blinded Placebo Controlled Trial.Saxena M, Sabado RL, La Mar M, Mohri H, Salazar AM, Dong H, Correa Da Rosa J, Markowitz M, Bhardwaj N, Miller E. Saxena M, et al. Front Immunol. 2019 Apr 9;10:725. doi: 10.3389/fimmu.2019.00725. eCollection 2019. Front Immunol. 2019. PMID: 31024557 Free PMC article. Clinical Trial.
- Serum Levels of Soluble CD40 Ligand and Neopterin in HIV Coinfected Asymptomatic and Symptomatic Visceral Leishmaniasis Patients.Adriaensen W, Abdellati S, van Henten S, Gedamu Y, Diro E, Vogt F, Mengesha B, Adem E, Kestens L, van Griensven J. Adriaensen W, et al. Front Cell Infect Microbiol. 2018 Dec 11;8:428. doi: 10.3389/fcimb.2018.00428. eCollection 2018. Front Cell Infect Microbiol. 2018. PMID: 30619775 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- CD40 Ligand / blood*
- Cells, Cultured
- Cross-Sectional Studies
- Dendritic Cells / immunology*
- HIV Infections / immunology*
- HIV-1 / immunology*
- Humans
- Interleukin-12 / immunology
- T-Lymphocytes, Regulatory / immunology
- Toll-Like Receptors / immunology
- Toll-Like Receptors
- CD40 Ligand
- Interleukin-12
- Full Text Sources
- Medical
- Research Materials
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![Figure 2. DCs incubated with sCD40L monomeric…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4478195/bin/nihms-678224-f0002.jpg)
Figure 3. DCs exposed to both monomeric…
Figure 3. DCs exposed to both monomeric and multimeric sCD40L induce IDO expression and regulatory…
Figure 4. DCs exposed to both monomeric…
Figure 4. DCs exposed to both monomeric and multimeric sCD40L induce anergy, which is not…
- Soluble CD40-ligand (sCD40L, sCD154) plays an immunosuppressive role via regulatory T cell expansion in HIV infection.Jenabian MA, Patel M, Kema I, Vyboh K, Kanagaratham C, Radzioch D, Thébault P, Lapointe R, Gilmore N, Ancuta P, Tremblay C, Routy JP. Jenabian MA, et al. Clin Exp Immunol. 2014 Oct;178(1):102-11. doi: 10.1111/cei.12396. Clin Exp Immunol. 2014. PMID: 24924152 Free PMC article.
- Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway.Miller EA, Spadaccia MR, OʼBrien MP, Rolnitzky L, Sabado R, Manches O, Frleta D, Bhardwaj N. Miller EA, et al. J Acquir Immune Defic Syndr. 2012 Dec 15;61(5):535-44. doi: 10.1097/QAI.0b013e31826afbce. J Acquir Immune Defic Syndr. 2012. PMID: 22902724 Free PMC article.
- Chronic immune activation in HIV-1 infection contributes to reduced interferon alpha production via enhanced CD40:CD40 ligand interaction.Donhauser N, Pritschet K, Helm M, Harrer T, Schuster P, Ries M, Bischof G, Vollmer J, Smola S, Schmidt B; German Competence Network HIV/AIDS. Donhauser N, et al. PLoS One. 2012;7(3):e33925. doi: 10.1371/journal.pone.0033925. Epub 2012 Mar 21. PLoS One. 2012. PMID: 22470494 Free PMC article.
- Dendritic cells at the interface of innate and adaptive immunity to HIV-1.Smed-Sörensen A, Loré K. Smed-Sörensen A, et al. Curr Opin HIV AIDS. 2011 Sep;6(5):405-10. doi: 10.1097/COH.0b013e328349b06b. Curr Opin HIV AIDS. 2011. PMID: 21743321 Review.
- Dendritic cell dysregulation during HIV-1 infection.Miller E, Bhardwaj N. Miller E, et al. Immunol Rev. 2013 Jul;254(1):170-89. doi: 10.1111/imr.12082. Immunol Rev. 2013. PMID: 23772620 Free PMC article. Review.
- Chronic Alcohol Exposure Among People Living with HIV Is Associated with Innate Immune Activation and Alterations in Monocyte Phenotype and Plasma Cytokine Profile.Underwood ML, Park B, Uebelhoer LS, Gu G, Kunkel LE, Korthuis PT, Cook RR, Sekaly RP, Ribeiro SP, Lancioni CL. Underwood ML, et al. Front Immunol. 2022 Mar 18;13:867937. doi: 10.3389/fimmu.2022.867937. eCollection 2022. Front Immunol. 2022. PMID: 35371104 Free PMC article.
- Dual Antiretroviral Therapy-All Quiet Beneath the Surface?van Welzen BJ, Oomen PGA, Hoepelman AIM. van Welzen BJ, et al. Front Immunol. 2021 Feb 12;12:637910. doi: 10.3389/fimmu.2021.637910. eCollection 2021. Front Immunol. 2021. PMID: 33643320 Free PMC article. Review.
- Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis.Lai JH, Luo SF, Ho LJ. Lai JH, et al. Cells. 2019 Aug 18;8(8):927. doi: 10.3390/cells8080927. Cells. 2019. PMID: 31426619 Free PMC article. Review.
- Poly-ICLC, a TLR3 Agonist, Induces Transient Innate Immune Responses in Patients With Treated HIV-Infection: A Randomized Double-Blinded Placebo Controlled Trial.Saxena M, Sabado RL, La Mar M, Mohri H, Salazar AM, Dong H, Correa Da Rosa J, Markowitz M, Bhardwaj N, Miller E. Saxena M, et al. Front Immunol. 2019 Apr 9;10:725. doi: 10.3389/fimmu.2019.00725. eCollection 2019. Front Immunol. 2019. PMID: 31024557 Free PMC article. Clinical Trial.
- Serum Levels of Soluble CD40 Ligand and Neopterin in HIV Coinfected Asymptomatic and Symptomatic Visceral Leishmaniasis Patients.Adriaensen W, Abdellati S, van Henten S, Gedamu Y, Diro E, Vogt F, Mengesha B, Adem E, Kestens L, van Griensven J. Adriaensen W, et al. Front Cell Infect Microbiol. 2018 Dec 11;8:428. doi: 10.3389/fcimb.2018.00428. eCollection 2018. Front Cell Infect Microbiol. 2018. PMID: 30619775 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- CD40 Ligand / blood*
- Cells, Cultured
- Cross-Sectional Studies
- Dendritic Cells / immunology*
- HIV Infections / immunology*
- HIV-1 / immunology*
- Humans
- Interleukin-12 / immunology
- T-Lymphocytes, Regulatory / immunology
- Toll-Like Receptors / immunology
- Toll-Like Receptors
- CD40 Ligand
- Interleukin-12
- Full Text Sources
- Medical
- Research Materials
![Figure 3. DCs exposed to both monomeric…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4478195/bin/nihms-678224-f0003.jpg)
![Figure 4. DCs exposed to both monomeric…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4478195/bin/nihms-678224-f0004.jpg)
Source: PubMed