Chronic immune activation and lymphocyte apoptosis during HIV-1 infection
Author: Ruffin, Nicolas
Date: 2012-02-17
Location: Föreläsningssalen vid Institutionen för Mikrobiologi, Tumör and Cellbiologi (MTC), Theorellsväg 1, Karolinska Institutet
Time: 09.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
Abstract
HIV-1 infected individuals are subject to a chronic immune activation resulting from HIV-1 replication, microbial translocation, and lymphopenia. Despite the great advance of antiretroviral treatment (ART), the immune activation remains associated with poor immune reconstitution during HIV-1 infection. The overall aim of this PhD thesis is to contribute to a better understanding of the causes and consequences of immune activation, possibly leading to the design of improved therapy for HIV-1 infected individuals.
Premature senescence of T cells, as a consequence of immune activation, is thought to be associated with the increased levels of CD28- T cells during HIV-1 infection. In Paper I, the phenotype and functional properties of CD28- T cells from HIV-1 individuals naïve to treatment, under ART and uninfected controls were assessed. Despite displaying similar markers of senescence, and late differentiation, we found that whereas CD28- T cells from untreated patients are highly susceptible to both spontaneous and activation-induced apoptosis, the same T cell population from ART-treated patients showed an enhanced capacity to proliferate upon weak TCR stimulation. Importantly, apoptosis of CD28- T cells from untreated patients was correlated with HIV-1 viral load, and their decreased ability to proliferate was associated with a reduced IL-2 production. High levels of CD28- T cells during HIV-1 infection might result from the chronic immune activation, whereas their sustained levels despite ART, is likely to arise from their capacity to proliferate under weak TCR signaling. Furthermore, with a capacity to produce IFN-γ, TNF and perforin, CD28- T cells from HIV-1 infected individuals might also contribute to the immune activation.
The mechanisms underlying the loss of memory B cells and the decline of serological memory during HIV-1 infection remain elusive. As microbial translocation and the associated immune activation have been shown to correlate with T cell depletion, we evaluated, in Paper II, the association between the serum levels of soluble CD14, a marker of microbial translocation, with the loss of resting memory B cells in HIV-1 infected individuals. Soluble CD14 levels were found to correlate with both the decline of resting memory B cells, and their increased expression of IL-21R. IL-21R expression on memory B cells was increased during HIV-1 infection, and also negatively correlated with the levels of circulating memory B cells. Notably, IL-21R positive memory B cells were more prone to apoptosis, measured by higher Annexin V staining and lower Bcl-2 expression, as compared to B cells lacking the receptor. Furthermore, TLR triggering by microbial products resulted in IL-21R expression on memory B cells in vitro. Our results identify a novel role for microbial translocation and the associated immune activation, contributing to the loss of memory B cells during HIV-1 infection.
Lymphopenic conditions are associated with increased IL-7. This cytokine involved in T cell homeostasis, is also found to be elevated in HIV-1 infected individuals concomitantly with low CD4+ T cell counts; although the regulation of IL-7 production is not fully understood in the context of HIV-1 infection. Using human intestinal epithelial (DLD-1) and bone marrow stromal (HS-27) cell lines, we investigated in Paper III, the consequence of pro-inflammatory cytokines on IL-7 production, measured at the mRNA and the protein levels. Whereas IFN-γ induced high IL-7 production in both cell lines, IL-1β treatment led to the opposite effect. We also analyzed the gene expression profiles of HS-27 cells treated with IL-1β and/or IFN-γ using the whole-genome microarray Human Gene 1.0 ST. Both cytokines resulted in enhanced expression of genes implicated in T cell immunity, particularly important during HIV-1 pathogenesis. Our results show that the immune activation can lead to profound change in stromal and epithelial cells, which in turn might shape immune responses.
While IL-7 is known to participate to T cell homeostasis, it has recently been shown that this cytokine possibly contribute to B cell defects, leading through IFN-γ release by T cells, to Fas up-regulation and sensitivity to Fas-mediated apoptosis. We further evaluated IL-7 regulation of T cell survival in Paper IV, and observed that B cells, co-cultured with IL-7 treated T cells, proliferated, displayed a phenotype of differentiated cells and secreted high levels of immunoglobulins (Igs). The Ig secretion was demonstrated to be a consequence of CD70 up-regulation on T cell upon IL-7 treatment. IL-7 led also to BAFF production by T cells, which enhanced B cell survival. In the context of HIV-1 infection, such mechanisms might be implicated in the B cell activation and hypergammaglobulinemia observed in patients.
Premature senescence of T cells, as a consequence of immune activation, is thought to be associated with the increased levels of CD28- T cells during HIV-1 infection. In Paper I, the phenotype and functional properties of CD28- T cells from HIV-1 individuals naïve to treatment, under ART and uninfected controls were assessed. Despite displaying similar markers of senescence, and late differentiation, we found that whereas CD28- T cells from untreated patients are highly susceptible to both spontaneous and activation-induced apoptosis, the same T cell population from ART-treated patients showed an enhanced capacity to proliferate upon weak TCR stimulation. Importantly, apoptosis of CD28- T cells from untreated patients was correlated with HIV-1 viral load, and their decreased ability to proliferate was associated with a reduced IL-2 production. High levels of CD28- T cells during HIV-1 infection might result from the chronic immune activation, whereas their sustained levels despite ART, is likely to arise from their capacity to proliferate under weak TCR signaling. Furthermore, with a capacity to produce IFN-γ, TNF and perforin, CD28- T cells from HIV-1 infected individuals might also contribute to the immune activation.
The mechanisms underlying the loss of memory B cells and the decline of serological memory during HIV-1 infection remain elusive. As microbial translocation and the associated immune activation have been shown to correlate with T cell depletion, we evaluated, in Paper II, the association between the serum levels of soluble CD14, a marker of microbial translocation, with the loss of resting memory B cells in HIV-1 infected individuals. Soluble CD14 levels were found to correlate with both the decline of resting memory B cells, and their increased expression of IL-21R. IL-21R expression on memory B cells was increased during HIV-1 infection, and also negatively correlated with the levels of circulating memory B cells. Notably, IL-21R positive memory B cells were more prone to apoptosis, measured by higher Annexin V staining and lower Bcl-2 expression, as compared to B cells lacking the receptor. Furthermore, TLR triggering by microbial products resulted in IL-21R expression on memory B cells in vitro. Our results identify a novel role for microbial translocation and the associated immune activation, contributing to the loss of memory B cells during HIV-1 infection.
Lymphopenic conditions are associated with increased IL-7. This cytokine involved in T cell homeostasis, is also found to be elevated in HIV-1 infected individuals concomitantly with low CD4+ T cell counts; although the regulation of IL-7 production is not fully understood in the context of HIV-1 infection. Using human intestinal epithelial (DLD-1) and bone marrow stromal (HS-27) cell lines, we investigated in Paper III, the consequence of pro-inflammatory cytokines on IL-7 production, measured at the mRNA and the protein levels. Whereas IFN-γ induced high IL-7 production in both cell lines, IL-1β treatment led to the opposite effect. We also analyzed the gene expression profiles of HS-27 cells treated with IL-1β and/or IFN-γ using the whole-genome microarray Human Gene 1.0 ST. Both cytokines resulted in enhanced expression of genes implicated in T cell immunity, particularly important during HIV-1 pathogenesis. Our results show that the immune activation can lead to profound change in stromal and epithelial cells, which in turn might shape immune responses.
While IL-7 is known to participate to T cell homeostasis, it has recently been shown that this cytokine possibly contribute to B cell defects, leading through IFN-γ release by T cells, to Fas up-regulation and sensitivity to Fas-mediated apoptosis. We further evaluated IL-7 regulation of T cell survival in Paper IV, and observed that B cells, co-cultured with IL-7 treated T cells, proliferated, displayed a phenotype of differentiated cells and secreted high levels of immunoglobulins (Igs). The Ig secretion was demonstrated to be a consequence of CD70 up-regulation on T cell upon IL-7 treatment. IL-7 led also to BAFF production by T cells, which enhanced B cell survival. In the context of HIV-1 infection, such mechanisms might be implicated in the B cell activation and hypergammaglobulinemia observed in patients.
List of papers:
I. Vivar N, Ruffin N, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Survival and Proliferation of CD28- T Cells during HIV-1 Infection Relates to the Amplitude of Viral Replication. J Infect Dis. 2011 Jun;203(11):1658-67.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ruffin N, Lantto R, Pensieroso S, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Immune Activation and IL-21 Receptor Expression are Associated with the Loss of Memory B-cells during HIV-1 infection. [Submitted]
III. Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F. The Role of IL-1beta in Reduced IL-7 Production by Stromal and Epithelial Cells: a Model for Impaired T-cell Numbers in the Gut during HIV-1 Infection. J Intern Med. 2010 Aug;268(2):1981-93.
Fulltext (DOI)
Pubmed
IV. Sammicheli S, Ruffin N, Lantto R, Vivar N, Chiodi F, Rethi B. IL-7 Promotes B cell Survival and Antibody Production by Inducing BAFF and CD70 Expression in T cells. J Autoimmun. [Accepted]
View record in Web of Science®
Pubmed
I. Vivar N, Ruffin N, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Survival and Proliferation of CD28- T Cells during HIV-1 Infection Relates to the Amplitude of Viral Replication. J Infect Dis. 2011 Jun;203(11):1658-67.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ruffin N, Lantto R, Pensieroso S, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Immune Activation and IL-21 Receptor Expression are Associated with the Loss of Memory B-cells during HIV-1 infection. [Submitted]
III. Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F. The Role of IL-1beta in Reduced IL-7 Production by Stromal and Epithelial Cells: a Model for Impaired T-cell Numbers in the Gut during HIV-1 Infection. J Intern Med. 2010 Aug;268(2):1981-93.
Fulltext (DOI)
Pubmed
IV. Sammicheli S, Ruffin N, Lantto R, Vivar N, Chiodi F, Rethi B. IL-7 Promotes B cell Survival and Antibody Production by Inducing BAFF and CD70 Expression in T cells. J Autoimmun. [Accepted]
View record in Web of Science®
Pubmed
Institution: Karolinska Institutet
Supervisor: Chiodi, Francesca
Issue date: 2012-01-26
Rights:
Publication year: 2012
ISBN: 978-91-7457-649-8
Statistics
Total Visits
Views | |
---|---|
Chronic ...(legacy) | 747 |
Chronic ... | 171 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Chronic ... | 0 | 1 | 0 | 0 | 4 | 0 | 0 |
File Visits
Views | |
---|---|
Thesis_Nicolas_Ruffin.pdf(legacy) | 517 |
Spikblad_Nicolas_Ruffin.pdf(legacy) | 226 |
Thesis_Nicolas_Ruffin.pdf | 208 |
Spikblad_Nicolas_Ruffin.pdf | 54 |
Spikblad_NR.pdf.txt(legacy) | 2 |
Thesis_NR.pdf.txt(legacy) | 2 |
Spikblad_Nicolas_Ruffin.pdf.txt(legacy) | 2 |
Thesis_Nicolas_Ruffin.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 394 |
China | 75 |
Sweden | 65 |
Germany | 52 |
South Korea | 44 |
France | 29 |
United Kingdom | 12 |
Finland | 8 |
Russia | 8 |
Hong Kong | 7 |
Top cities views
Views | |
---|---|
Ashburn | 50 |
Sunnyvale | 36 |
Romeo | 25 |
Daejeon | 21 |
Seoul | 20 |
Beijing | 19 |
Kiez | 19 |
Stockholm | 12 |
Mountain View | 11 |
Saint Maurice | 10 |