Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Nov;5(6):646-57.
doi: 10.1038/mi.2012.38. Epub 2012 May 30.

Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection

N R Klatt  1 , J D Estes, X Sun, A M Ortiz, J S Barber, L D Harris, B Cervasi, L K Yokomizo, L Pan, C L Vinton, B Tabb, L A Canary, Q Dang, V M Hirsch, G Alter, Y Belkaid, J D Lifson, G Silvestri, J D Milner, M Paiardini, E K Haddad, J M Brenchley
Affiliations

Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection

N R Klatt et al. Mucosal Immunol. 2012 Nov.

Abstract

Human immunodeficiency virus (HIV) and Simian immunodeficiency virus (SIV) disease progression is associated with multifocal damage to the gastrointestinal tract epithelial barrier that correlates with microbial translocation and persistent pathological immune activation, but the underlying mechanisms remain unclear. Investigating alterations in mucosal immunity during SIV infection, we found that damage to the colonic epithelial barrier was associated with loss of multiple lineages of interleukin (IL)-17-producing lymphocytes, cells that microarray analysis showed expressed genes important for enterocyte homeostasis, including IL-22. IL-22-producing lymphocytes were also lost after SIV infection. Potentially explaining coordinate loss of these distinct populations, we also observed loss of CD103+ dendritic cells (DCs) after SIV infection, which associated with the loss of IL-17- and IL-22-producing lymphocytes. CD103+ DCs expressed genes associated with promotion of IL-17/IL-22+ cells, and coculture of CD103+ DCs and naïve T cells led to increased IL17A and RORc expression in differentiating T cells. These results reveal complex interactions between mucosal immune cell subsets providing potential mechanistic insights into mechanisms of mucosal immune dysregulation during HIV/SIV infection, and offer hints for development of novel therapeutic strategies to address this aspect of AIDS virus pathogenesis.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Loss of IL-17-producing lymphocytes correlates with damage to the tight epithelial barrier of the colon
The frequency of IL-17-producing CD4+ T cells in (a) colon, and (b) MLNs, IL-17-producing CD8+ T cells in (c) colon, and (d) MLNs, and IL-17-producing CD3-CD8+ lymphocytes in (e) colon and (f) MLNs were compared to the extent of damage to the structural barrier of the colonic epithelium as measured by the breach (no claudin) to intact (claudin) ratio. Circles, SIV-; Triangles, SIV+. Diagonal lines represent linear regression.
Figure 2
Figure 2. IL-17-producing lymphocytes upregulate genes essential for mucosal homeostasis
(a) The top 200 genes based on P value for the greatest contrast between IL17+ and IL17− lymphocytes from MLNs of SIV-uninfected RM. The complete linkage method was used for hierarchical cluster analysis. Both rows and columns are clustered. Each row represents normalized expression value for a single gene, and each column represents a sample (data are based upon RNA extractions from IL17+ lymphocytes from 2 SIV-uninfected RM, left, and IL17− lymphocytes from 3 SIV-uninfected RM, right). (b) Fold change of selected genes that were up-regulated by IL-17+ lymphocytes (top) or IL-17− lymphocytes (bottom). P values donated above each gene fold change. (c-d) The network (c) and pathway (d) from IPA analysis for selected genes is shown. Red indicates up-regulation (fold change >= 1.5); green indicates down-regulation (fold change <= −1.5); grey indicates genes whose expression values are between −1.5 and 1.5. (c) Shape: triangle represents kinase; square represents cytokine; rectangle represents ligand-dependent nuclear receptor; diamond represents enzyme; trapezoid represents transporter; ellipse represents transcription regulator; circle represents others.
Figure 3
Figure 3. IL-17-producing lymphocytes produce IL-22, and IL-22-producing lymphocytes are lost after SIV infection and associated with mucosal barrier integrity
(a-b) The frequency of IL-22+ cells within IL-17-producing CD4+ T cells (left), CD8+ T cells (center) and CD3-CD8+ lymphocytes (right) in (a) colon, and (b) MLNs. (c-d) The frequency of IL-22-producing CD4+ T cells (left), CD8+ T cells (center) and CD3-CD8+ lymphocytes (right) in uninfected (circles) or SIV-infected (triangles) RMs in (c) colon and (d) MLNs. (e-f) The frequency of IL-22-producing CD4+ T cells (left), CD8+ T cells (center) and CD3-CD8+ lymphocytes (right) in (e) colon and (f) MLNs were compared to damage to the structural barrier of the colon as measured by the breach (no claudin) to intact (claudin) ratio. Closed circles, SIV− colon; closed triangles, SIV+ colon; open circles, SIV− MLNs; open triangles, SIV+ MLNs. Horizontal bars represent median, diagonal lines represent linear regression.
Figure 4
Figure 4. CD103+ DCs are lost after SIV infection, and associated with the frequency of IL-17 and IL-22-producing lymphocytes
(a-b) The frequency of live, lineage-, HLA-DR+ CD103+ DCs in the colon (a) or MLNs (b). (c-e) The frequency of CD103+ DCs is compared to the frequency of IL-17-producing CD4+ T cells (c), CD8+ T cells (d) or CD3-CD8+ lymphocytes (e). The frequency of CD103+ DCs is compared to the frequency of IL-22-producing CD4+ T cells (c), CD8+ T cells (d) or CD3-CD8+ lymphocytes (e). Closed circles, SIV− colon; closed triangles, SIV+ colon; open circles, SIV− MLNs; open triangles, SIV+ MLNs. Horizontal bars represent median, diagonal lines represent linear regression.
Figure 5
Figure 5. CD103+ DCs upregulate IL-17 promoting genes
(a) The top 200 genes based on P value for the contrast between CD103+CD11c DCs and CD103-CD11c+ DCs from MLNs of SIV-uninfected RM. The complete linkage method was used for hierarchical cluster analysis. Both rows and columns are clustered. Each row represents normalized expression value for a single gene, and each column represents a sample (data are from MLS of 3 SIV-uninfected animals and CD103+CD11c− DCs are left and CD103-CD11c+ DCs are right). (b) Fold change of selected genes that were upregulated in CD103+ DCs (top) or CD103-CD11c+ DCs (bottom). P values donated above each gene fold change. (c) The network from IPA analysis for selected genes is shown. Color: red indicates up-regulation (fold change >= 1.5); green indicates down-regulation (fold change <= −1.5); grey indicates the genes whose expression values are between −1.5 and 1.5. Shape: triangle represents kinase; square represents cytokine; rectangle represents ligand-dependent nuclear receptor; diamond represents enzyme; trapezoid represents transporter; ellipse represents transcription regulator; circle represents others.
Figure 6
Figure 6. CD103+ DCs directly promote IL17A and RORc expression by naïve CD4+ T cells
Naïve CD4+ T cells were co-cultured under Th17 conditions with stimulatory anti-CD3 beads alone (control), with CD103+ DCs, or with CD103− DCs in the presence of IL-6 (a, c) or absence of IL-6 (b, d). Gene expression for IL17A (a-b) and RORc (c-d) was measured by ΔΔCt compared to controls. Cells were sorted from live, SIV− rhesus macaque mesenteric lymph nodes. Rh1 and Rh2 designate the two rhesus macaques used for this experiment.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Estes JD, et al. Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections. PLoS Pathog. 2010;6:e1001052. - PMC - PubMed
    1. Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1:23–30. - PMC - PubMed
    1. Brenchley JM, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–1371. - PubMed
    1. Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol. 2006;7:235–239. - PubMed
    1. Ancuta P, et al. Microbial Translocation Is Associated with Increased Monocyte Activation and Dementia in AIDS Patients. PLoS ONE. 2008;3:e2516. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources