Limits...
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.

Show MeSH

Related in: MedlinePlus

Cytokine profiles of dermis-derived CD4 and CD8 bulk T cell populations.Relative contribution of T cells with different expression profiles of IL-17A, IL-22 and IFN-γ production among in vitro activated dermal CD4 T cells (a) and CD8 T (b) from psoriatic skin (closed symbols) versus normal skin (open symbols). Each series of a particular symbol represents data from one individual. Specifically T cells with the ability to produce IL-17A and/or IL-22 are present in increased percentages of the CD8 T cell population in lesional skin compared to normal skin. *P<0.05; **P<0.01 Depicted data show the results obtained by six color flow cytometry of the eight independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2991333&req=5

pone-0014108-g003: Cytokine profiles of dermis-derived CD4 and CD8 bulk T cell populations.Relative contribution of T cells with different expression profiles of IL-17A, IL-22 and IFN-γ production among in vitro activated dermal CD4 T cells (a) and CD8 T (b) from psoriatic skin (closed symbols) versus normal skin (open symbols). Each series of a particular symbol represents data from one individual. Specifically T cells with the ability to produce IL-17A and/or IL-22 are present in increased percentages of the CD8 T cell population in lesional skin compared to normal skin. *P<0.05; **P<0.01 Depicted data show the results obtained by six color flow cytometry of the eight independent experiments.

Mentions: We were able to detect only an occasional IL-17pos and no IL-22pos T cell in lesional psoriatic skin in situ, but one should consider that T cells only temporarily express cytokines upon activation, that intralesional T cells are unlikely to be all in the same phase of activation, and that T cells are most likely in a resting stage in normal skin. Consequently, in situ analysis of cytokine expression by T cells probably represents an underestimation of the percentage T cells with the ability to produce a cytokine of interest. As an alternative approach to gain insight into the percentages of IL-17A and IL-22 producing T cells, we isolated T cells which spontaneously migrated from cultured dermal and epidermal skin fragments and determined their ability to produce these cytokines upon mitogenic activation in vitro. In addition, we also studied the production of IFN-γ. Six color flow cytometry was performed to study the simultaneous expression of CD3, CD4, CD8, IL-17A, IL-22 and IFN-γ by individual cells. Representative cytokine expression profiles of CD3 populations from the dermal component of psoriatic and normal skin are shown in the FACS dot plots in Figure 2. The proportions of dermal CD4 and CD8 T cells expressing distinct cytokine profiles are shown in Figure 3. Dermal T cells derived from psoriatic skin, as well as from normal skin, consistently contained a substantial percentage of IL-17A producers, indicating that the presence of IL-17Apos T cells is not restricted to lesional skin (Figures 2 and 3). Some IL-17Apos T cells coproduced IL-22, consistent with what has been described for mouse as well as human Th17 cells. On the other hand, all dermal T cell samples from both lesional and normal skin contained T cells which produced IL-22 in the absence of IL-17A and IFN-γ, representing the recently defined Th22 cells and their CD8 “Tc22” counterparts (Figures 2 and 3). Only a minority of IL-17A and/or IL-22 producing T cells displayed IFN-γ production as well and could be distinguished in most samples (Figures 2 and 3). T cells producing IFN-γ in the absence of IL-17A and IL-22, in our study referred to as Th1 and Tc1 cells, accounted for the highest percentage of dermal T cells in both lesional and normal skin (Figures 2 and 3).


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 profiles of dermis-derived CD4 and CD8 bulk T cell populations.Relative contribution of T cells with different expression profiles of IL-17A, IL-22 and IFN-γ production among in vitro activated dermal CD4 T cells (a) and CD8 T (b) from psoriatic skin (closed symbols) versus normal skin (open symbols). Each series of a particular symbol represents data from one individual. Specifically T cells with the ability to produce IL-17A and/or IL-22 are present in increased percentages of the CD8 T cell population in lesional skin compared to normal skin. *P<0.05; **P<0.01 Depicted data show the results obtained by six color flow cytometry of the eight independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991333&req=5

pone-0014108-g003: Cytokine profiles of dermis-derived CD4 and CD8 bulk T cell populations.Relative contribution of T cells with different expression profiles of IL-17A, IL-22 and IFN-γ production among in vitro activated dermal CD4 T cells (a) and CD8 T (b) from psoriatic skin (closed symbols) versus normal skin (open symbols). Each series of a particular symbol represents data from one individual. Specifically T cells with the ability to produce IL-17A and/or IL-22 are present in increased percentages of the CD8 T cell population in lesional skin compared to normal skin. *P<0.05; **P<0.01 Depicted data show the results obtained by six color flow cytometry of the eight independent experiments.
Mentions: We were able to detect only an occasional IL-17pos and no IL-22pos T cell in lesional psoriatic skin in situ, but one should consider that T cells only temporarily express cytokines upon activation, that intralesional T cells are unlikely to be all in the same phase of activation, and that T cells are most likely in a resting stage in normal skin. Consequently, in situ analysis of cytokine expression by T cells probably represents an underestimation of the percentage T cells with the ability to produce a cytokine of interest. As an alternative approach to gain insight into the percentages of IL-17A and IL-22 producing T cells, we isolated T cells which spontaneously migrated from cultured dermal and epidermal skin fragments and determined their ability to produce these cytokines upon mitogenic activation in vitro. In addition, we also studied the production of IFN-γ. Six color flow cytometry was performed to study the simultaneous expression of CD3, CD4, CD8, IL-17A, IL-22 and IFN-γ by individual cells. Representative cytokine expression profiles of CD3 populations from the dermal component of psoriatic and normal skin are shown in the FACS dot plots in Figure 2. The proportions of dermal CD4 and CD8 T cells expressing distinct cytokine profiles are shown in Figure 3. Dermal T cells derived from psoriatic skin, as well as from normal skin, consistently contained a substantial percentage of IL-17A producers, indicating that the presence of IL-17Apos T cells is not restricted to lesional skin (Figures 2 and 3). Some IL-17Apos T cells coproduced IL-22, consistent with what has been described for mouse as well as human Th17 cells. On the other hand, all dermal T cell samples from both lesional and normal skin contained T cells which produced IL-22 in the absence of IL-17A and IFN-γ, representing the recently defined Th22 cells and their CD8 “Tc22” counterparts (Figures 2 and 3). Only a minority of IL-17A and/or IL-22 producing T cells displayed IFN-γ production as well and could be distinguished in most samples (Figures 2 and 3). T cells producing IFN-γ in the absence of IL-17A and IL-22, in our study referred to as Th1 and Tc1 cells, accounted for the highest percentage of dermal T cells in both lesional and normal skin (Figures 2 and 3).

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