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Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.

Res PC, Piskin G, de Boer OJ, van der Loos CM, Teeling P, Bos JD, Teunissen MB - PLoS ONE (2010)

Bottom Line: Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin.Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin.Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. p.c.res@amc.uva.nl

ABSTRACT

Background: Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ.

Methodology/principal findings: By spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-γ (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well.

Conclusions/significance: The increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17A(pos) CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cells.

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Cytokine profile of psoriatic skin derived Th17 and Tc17 clones.IL-17Apos CD4 and CD8 T cell clones (Th17 and Tc17, respectively) from psoriatic skin have the ability to give rise to a proportion of IL-22 producing cells that lack IL-17A and IFN-γ expression (the putative Th22 and Tc22, respectively). IL-17Apos CD4 dermal T cells and CD8 epidermal T cells derived from psoriatic skin were cloned and subsequently assayed for intracellular IL-17A, IL-22, and IFN-γ after PMA ionomycin stimulation. Representative examples of CD4 and CD8 T cell clones are given. Part of the cells within the CD4 Th17 clone expressed IL-22, but lacked both IL-17A (right-bottom quadrant in the upper dot-plot) and IFN-γ expression (associated histogram indicated by arrow), a cytokine pattern typical of Th22 cells. Likewise, part of the cells of the CD8 Tc17 clone (bottom dot-plot) lacked IL-17A and IFN-γ expression, which is a Tc22 cytokine profile.
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pone-0014108-g005: Cytokine profile of psoriatic skin derived Th17 and Tc17 clones.IL-17Apos CD4 and CD8 T cell clones (Th17 and Tc17, respectively) from psoriatic skin have the ability to give rise to a proportion of IL-22 producing cells that lack IL-17A and IFN-γ expression (the putative Th22 and Tc22, respectively). IL-17Apos CD4 dermal T cells and CD8 epidermal T cells derived from psoriatic skin were cloned and subsequently assayed for intracellular IL-17A, IL-22, and IFN-γ after PMA ionomycin stimulation. Representative examples of CD4 and CD8 T cell clones are given. Part of the cells within the CD4 Th17 clone expressed IL-22, but lacked both IL-17A (right-bottom quadrant in the upper dot-plot) and IFN-γ expression (associated histogram indicated by arrow), a cytokine pattern typical of Th22 cells. Likewise, part of the cells of the CD8 Tc17 clone (bottom dot-plot) lacked IL-17A and IFN-γ expression, which is a Tc22 cytokine profile.

Mentions: One may question whether the cytokine patterns of the skin-infiltrating T cells are stable and transferred to the progeny after cell division. To investigate this for IL-17A producers in particular, we cloned psoriatic dermal Th17 cells which were purified by FACS sorting on the basis of an IL-17A release-capture assay. This technique could not be used when we cloned T cells from the corresponding epidermis, because of the limited number of epidermal T cells. In that case we purified T cells on basis of CD8 cell surface expression and twelve out of fifteen of the epidermal CD8 T cell clones turned out be IL-17A producers, consistent with our observation that epidermal CD8 T cells from psoriatic skin contain high percentages of Tc17 cells. The remaining three epidermal T cell clones expressed IFN-γ only, without IL-17A or IL-22, thus representing Tc1 clones. All cells within individual clones displayed the same T cell receptor V-beta family usage confirming clonality (data not shown). Twelve CD4 T cell clones, each originating from a different single IL-17A-expressing T cell, were found to still produce IL-17A after culture for one month. Unexpectedly however, in five of these Th17 clones a variable proportion (range 5–25%) of cells did produce IL-22 but lacked IL-17A, and in addition, part of these IL-17AnegIL-22pos T cells lacked IFN-γ as well, indicating that some cells had acquired a Th22 profile (Figure 5). This suggests a developmental relationship between Th17 and Th22 cells and it is not inconceivable that Th22 cells may originate from Th17 precursors in vivo. Likewise, a proportion of cells with a Tc22 cytokine profile were found in six out of twelve of the IL-17A producing epidermal CD8 T cell clones derived from the same skin biopsy (Figure 5). Taken all together, our results suggest that CD4 and CD8 T cells in psoriatic skin have a certain degree of plasticity in their cytokine production pattern.


Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.

Res PC, Piskin G, de Boer OJ, van der Loos CM, Teeling P, Bos JD, Teunissen MB - PLoS ONE (2010)

Cytokine profile of psoriatic skin derived Th17 and Tc17 clones.IL-17Apos CD4 and CD8 T cell clones (Th17 and Tc17, respectively) from psoriatic skin have the ability to give rise to a proportion of IL-22 producing cells that lack IL-17A and IFN-γ expression (the putative Th22 and Tc22, respectively). IL-17Apos CD4 dermal T cells and CD8 epidermal T cells derived from psoriatic skin were cloned and subsequently assayed for intracellular IL-17A, IL-22, and IFN-γ after PMA ionomycin stimulation. Representative examples of CD4 and CD8 T cell clones are given. Part of the cells within the CD4 Th17 clone expressed IL-22, but lacked both IL-17A (right-bottom quadrant in the upper dot-plot) and IFN-γ expression (associated histogram indicated by arrow), a cytokine pattern typical of Th22 cells. Likewise, part of the cells of the CD8 Tc17 clone (bottom dot-plot) lacked IL-17A and IFN-γ expression, which is a Tc22 cytokine profile.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991333&req=5

pone-0014108-g005: Cytokine profile of psoriatic skin derived Th17 and Tc17 clones.IL-17Apos CD4 and CD8 T cell clones (Th17 and Tc17, respectively) from psoriatic skin have the ability to give rise to a proportion of IL-22 producing cells that lack IL-17A and IFN-γ expression (the putative Th22 and Tc22, respectively). IL-17Apos CD4 dermal T cells and CD8 epidermal T cells derived from psoriatic skin were cloned and subsequently assayed for intracellular IL-17A, IL-22, and IFN-γ after PMA ionomycin stimulation. Representative examples of CD4 and CD8 T cell clones are given. Part of the cells within the CD4 Th17 clone expressed IL-22, but lacked both IL-17A (right-bottom quadrant in the upper dot-plot) and IFN-γ expression (associated histogram indicated by arrow), a cytokine pattern typical of Th22 cells. Likewise, part of the cells of the CD8 Tc17 clone (bottom dot-plot) lacked IL-17A and IFN-γ expression, which is a Tc22 cytokine profile.
Mentions: One may question whether the cytokine patterns of the skin-infiltrating T cells are stable and transferred to the progeny after cell division. To investigate this for IL-17A producers in particular, we cloned psoriatic dermal Th17 cells which were purified by FACS sorting on the basis of an IL-17A release-capture assay. This technique could not be used when we cloned T cells from the corresponding epidermis, because of the limited number of epidermal T cells. In that case we purified T cells on basis of CD8 cell surface expression and twelve out of fifteen of the epidermal CD8 T cell clones turned out be IL-17A producers, consistent with our observation that epidermal CD8 T cells from psoriatic skin contain high percentages of Tc17 cells. The remaining three epidermal T cell clones expressed IFN-γ only, without IL-17A or IL-22, thus representing Tc1 clones. All cells within individual clones displayed the same T cell receptor V-beta family usage confirming clonality (data not shown). Twelve CD4 T cell clones, each originating from a different single IL-17A-expressing T cell, were found to still produce IL-17A after culture for one month. Unexpectedly however, in five of these Th17 clones a variable proportion (range 5–25%) of cells did produce IL-22 but lacked IL-17A, and in addition, part of these IL-17AnegIL-22pos T cells lacked IFN-γ as well, indicating that some cells had acquired a Th22 profile (Figure 5). This suggests a developmental relationship between Th17 and Th22 cells and it is not inconceivable that Th22 cells may originate from Th17 precursors in vivo. Likewise, a proportion of cells with a Tc22 cytokine profile were found in six out of twelve of the IL-17A producing epidermal CD8 T cell clones derived from the same skin biopsy (Figure 5). Taken all together, our results suggest that CD4 and CD8 T cells in psoriatic skin have a certain degree of plasticity in their cytokine production pattern.

Bottom Line: Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin.Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin.Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. p.c.res@amc.uva.nl

ABSTRACT

Background: Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ.

Methodology/principal findings: By spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-γ (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well.

Conclusions/significance: The increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17A(pos) CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cells.

Show MeSH
Related in: MedlinePlus