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. 2019 Jan 24;9(1):762.
doi: 10.1038/s41598-018-37144-y.

Impaired activation of lesional CD8+ T-cells is associated with enhanced expression of Programmed Death-1 in Indian Post Kala-azar Dermal Leishmaniasis

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Impaired activation of lesional CD8+ T-cells is associated with enhanced expression of Programmed Death-1 in Indian Post Kala-azar Dermal Leishmaniasis

Shibabrata Mukherjee et al. Sci Rep. .

Erratum in

Abstract

Post Kala-azar dermal leishmaniasis (PKDL), caused by Leishmania donovani is the dermal sequel of Visceral Leishmaniasis and importantly, is the proposed disease reservoir. The survival of Leishmania parasites within monocytes/macrophages hinges on its ability to effectively nullify immune activation mechanisms. Thus, delineating the disease-promoting immune mechanisms can facilitate development of immunotherapeutic strategies. Accordingly, in the absence of an animal model, this study aimed to delineate the status of CD8+ T-cells in patients with PKDL. At disease presentation, the absence of CD4+ T-cells at lesional sites was concomitant with an overwhelming infiltration of CD8+ T-cells that demonstrated an absence of Perforin, Granzyme and Zap-70, along with an enhanced expression of Programmed Death-1 (PD-1) and the skin-homing CCL17. Additionally, the lesional CCR4+CD8+ population was associated with an enhanced expression of IL-10 and IL-5. In circulation, the enhanced CD8+CCR4+ T-cell population and raised levels of CCL17/22 was associated with an increased frequency of PD-1, while CD127 was decreased. Taken together, in PKDL, the enhanced plasma and lesional CCL17 accounted for the dermal homing of CD8+CCR4+ T-cells, that along with a concomitant upregulation of PD-1 and IL-10 mediated immune inactivation, emphasizing the need for designing immunotherapies capable of reinvigorating T-cell potency.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Distribution of T-cells in dermal lesions of patients with PKDL. (a) Representative immunohistochemical profiles of CD4+ T-cells from dermal biopsies of a healthy control, patient with PKDL and post treatment (10X magnification). (b) Scatter plots of CD4+ T-cells in dermal biopsies of healthy controls (●くろまる, n = 5) patients with PKDL (■しかく, n = 10) and post treatment (▲さんかく, n = 10). Each horizontal bar represents the median value. (c,d) Representative immunohistochemical profiles of CD8+ T-cells from dermal biopsies of a healthy control, patient with PKDL and post treatment (10X and 40X magnification). (e) Scatter plots of CD8+ T-cells in dermal biopsies of healthy controls (●くろまる, n = 5) patients with PKDL (■しかく, n = 9) and post treatment (▲さんかく, n = 9). Each horizontal bar represents the median value. (f) Before (●くろまる) and after (○しろまる) treatment plots of CD8+ T-cells.
Figure 2
Figure 2
Dermal homing of CD8+ T-cells in patients with PKDL. (a) Representative immunohistochemical profiles of CCL17+ cells from dermal biopsies of a healthy control, patient with PKDL and post treatment (100X magnification). (b) Scatter plots showing the status of dermal CCL17+ cells in healthy controls (●くろまる, n = 5), patients with PKDL at presentation (■しかく, n = 10), and post treatment (▲さんかく, n = 10), along with before (●くろまる) and after (○しろまる) treatment plots. Each horizontal bar represents the median value. (c) Scatter plots showing plasma levels of CCL17 and CCL22 in healthy controls (●くろまる, n = 9 for CCL17, n = 10 for CCL22), patients with PKDL (■しかく, n = 12), and post treatment (▲さんかく, n = 10); each horizontal bar represents the median value. Before (●くろまる) and after (○しろまる) treatment plots of CCL17 and CCL22.
Figure 3
Figure 3
Status of Chemokine Receptor 4 (CCR4) in CD8+ T-cells in patients with PKDL. (a) Representative immunohistochemical profiles of CCR4+ T-cells from dermal biopsies of a healthy control, patient with PKDL and post treatment (10X magnification). Scatter plots showing the status of dermal CCR4+ cells in healthy controls (●くろまる, n = 5), patients with PKDL (■しかく, n = 9), and post treatment (▲さんかく, n = 9), along with before (●くろまる) and after (○しろまる) treatment plots. Each horizontal bar represents the median value. (b) Representative immunohistochemical profiles of CD8+CCR4+ T-cells from dermal biopsies of a patient with PKDL and post treatment (100X magnification); in the co-localization stain, red denotes the CD8 staining and brown denotes the CCR4 stain, along with scatter plots of CD8+CCR4+T-cells at disease presentation (●くろまる, n = 6) and post treatment (■しかく, n = 6). Each horizontal bar represents the median value. Correlation of CD8+CCR4+ T-cells with plasma levels of CCL 17 and CCL 22 respectively. (c) Representative quadrant plots of CD8+CCR4+ T-cells in peripheral blood of a healthy control and a patient with PKDL. Scatter plot of CCR4+ cells in CD8+ T-cells of healthy controls (●くろまる, n = 10) and at disease presentation (■しかく, n = 10). The proportion of CCR4+ cells in the entire CD8+ population was calculated by dividing the percentages of upper right quadrant by the sum of the upper and lower right quadrant. Each horizontal bar represents the median value.
Figure 4
Figure 4
Activation status of lesional and peripheral CD8+ T-cells in patients with PKDL. (a–c) Representative immunohistochemical profiles of Perforin (a), Granzyme (b) and Zap70 (c) in dermal biopsies of a healthy control, patient with PKDL (10X magnification); a reactive lymph node served as the positive control (40X magnification). (d) Representative quadrant plots indicating frequency (%) of CD127+ within CD8+ T-cells in peripheral blood of a healthy control, patient with PKDL and post treatment. (e) Scatter plots showing frequency (%) of CD127+ within CD8+ T-cells of healthy controls (●くろまる, n = 9), patients with PKDL (■しかく, n = 10) and post treatment (▲さんかく, n = 9). The proportion of CD127+ within the entire CD8+ population was calculated by dividing the percentages of upper right quadrant by the sum of upper and lower right quadrant. Each horizontal bar represents the median value. Before (●くろまる) and after (○しろまる) treatment plots of CD127+ in CD8+ T-cells in patients with PKDL.
Figure 5
Figure 5
Presence of Programmed Death-1 (PD-1) in dermal lesions and circulation of patients with PKDL. (a) Representative mRNA expression profiles of PD-1 (cropped from original gel images, full-length gels are presented in Supplementary Fig. S6) in dermal biopsies of healthy controls (N1–3), patients with PKDL (Pre1–3) and post treatment (Post1–3). Scatter plots of PD-1 in healthy controls (●くろまる, n = 5), at disease presentation (■しかく, n = 10) and post treatment (▲さんかく, n = 10). Each horizontal bar represents the median value. Before (●くろまる) and after (○しろまる) treatment plots of PD-1. (b) Representative immunohistochemical profiles of PD-1+ cells from dermal biopsies of a healthy control, patient with PKDL and post treatment (10X and 40X magnification). Scatter plots of PD-1+ cells in dermal biopsies of healthy controls (●くろまる, n = 5) patients with PKDL (■しかく, n = 9) and post treatment (▲さんかく, n = 9). Each horizontal bar represents the median value. Before (●くろまる) and after treatment (○しろまる) plots of PD-1+ cells. (c) Representative quadrant plots indicating the frequency (%) of PD-1+ within CD8+ T-cells in peripheral blood of a healthy control, patient with PKDL and post treatment. (d) Scatter plots of PD-1+ in CD8+ T-cells of healthy controls (●くろまる, n = 10), at disease presentation (■しかく, n = 10) and post treatment (▲さんかく, n = 10). Each horizontal bar represents the median value. The proportion of PD-1+ in the entire CD8+ population was calculated by dividing percentages of the upper right quadrant by the sum of upper and lower right quadrant. (e) Before (●くろまる) and after treatment (○しろまる) plots of PD-1+ in CD8+ T-cells.
Figure 6
Figure 6
Distribution of IL-10 and IL-5 in dermal lesions of patients with PKDL. (a) Representative immunohistochemical profiles of IL-10 from dermal biopsies of a healthy control, a patient with PKDL and post treatment (40X magnification). (b) Representative immunohistochemical profiles of IL-5 from dermal biopsies of a healthy control, a patient with PKDL and post treatment (10X and 40X magnification). (c) Scatter plots showing distribution of IL-5+ cells in healthy controls (●くろまる, n = 5), at disease presentation (■しかく, n = 10) and post treatment (▲さんかく, n = 10). Each horizontal bar represents the median value. Before (●くろまる) and after (○しろまる) treatment plots of IL-5+ cells.
Figure 7
Figure 7
Cellular interactions between peripheral blood and dermal lesions in patients with PKDL. In patients with PKDL, the increased presence of CCL17/22 upon interaction with CCR4 paved the way for homing of CD8+ T-cells to the dermal lesional sites. These CD8+ T-cells showed exhaustion as confirmed by the increased presence of PD-1 in peripheral blood and dermal lesions, which benefitted from the milieu generated by the increased presence of IL-4/IL-5 and IL-10.

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