Cd8αα+T Cells Exert a Pro-inflammatory Role in Patients With Psoriasis&nbsp;

doi:10.21203/rs.3.rs-199130/v1

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Cd8αα+T Cells Exert a Pro-inflammatory Role in Patients With Psoriasis

https://doi.org/10.21203/rs.3.rs-199130/v1

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Psoriasis is a common chronic inflammatory disease caused by excessive activation of CD4⁺T cells, including Th17, Th1, and Th22. The role of CD8⁺T cells in psoriasis pathogenesis remains poorly understood. In this study, we aimed to identify the phenotype of CD8⁺T cells in patients with psoriasis and to investigate its role in the formation of lesions. First of all, we identify CD8αα⁺T cell as a main subset of CD8⁺T cells infiltrated in lesions of patients with psoriasis. Furthermore, we found that epidermal CD8αα⁺T cells exhibited tissue-resident memory T cells (T_RM) phenotypes and dermal CD8αα⁺T cells exhibited effector memory (T_EM) phenotypes in psoriatic lesions. Thereafter, by coculturing CD8αα⁺T cells with autogenous CD4⁺T cells to investigate the function of CD8αα⁺T cells, we found that CD8αα⁺T cells from patients with psoriasis could promote the proliferation of CD4⁺T effector cells; while CD8αα⁺T cells from healthy controls exerted immunosuppressive function. Finally, we demonstrate that CD8αα⁺T cells from patients with psoriasis did not express the markers of regulatory T cells, and produce IL-17 and IFN-γ. In conclusion, our findings demonstrate that CD8αα⁺T cells contribute to the pathogenesis of psoriasis by producing pro-inflammatory factors.

Dermatology

Psoriasis

CD8+T cells

CD8αα

Tissue-resident memory T cells

Psoriasis is a common T cell-mediated chronic inflammatory disorder. It is generally accepted that excessive activation of CD4⁺T cells is critical for psoriasis pathogenesis via production of interleukin-17 (IL-17), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) ¹. Recent studies have shown that in addition to CD4⁺T cells, γδT cells, dendritic cells, neutrophils and CD8⁺T cells are also found to produce pro-inflammatory factors in patients with psoriasis ^2-4.

CD4 and CD8 are expressed on the surface of T cells as co-receptors to enhance sensitivity to antigens. CD8 is different from CD4 in that it functions as a dimer, including homodimer CD8αα and heterodimer CD8αβ. CD8αα has been found in different immune cells, including T cells, dendritic cells, and natural killing cells ^5,6. CD8αβ is specifically expressed in T cells, which is called cytotoxic T cells. CD8αβ is a superior T-cell coreceptor that recruits T-cell receptors (TCRs) to lipid rafts and enhances the interaction of TCR-CD3 activation complexes with the major histocompatibility complex (MHC) class I. However, CD8αα is excluded from lipid rafts and negatively regulates TCR activation by disrupting lipid rafts and sequestering signaling molecules required for TCR-initiated downstream signaling ^7,8.

Previous studies have shown that CD8αα⁺T cells are found in the gut epithelium and can interact with intestinal epithelial cells by CD8αα binding to Thymus leukemia (TL, non-classical MHC class I molecules). CD8αα⁺T cells function as regulatory T cells in the intestinal mucosa, although, they do not express Foxp3 ^9,10. Additionally, unlike CD8αβ⁺T cells, TCR of CD8αα⁺T cells is oligoclonal and recognizes peptide fragments from T cell receptors or MHC. Thus, CD8αα⁺T cells exert a suppressive role by targeting effector T cells or antigen-presenting cells ¹¹. However, whether CD8αα⁺T cells contribute to the pathogenesis of psoriasis has not been clarified. In our study, we investigate the phenotypes of CD8αα⁺T cells in patients with psoriasis and its role in lesion formation.

Increased CD8αα⁺T cells located in psoriatic lesions

Previous studies have shown that CD8⁺T cells infiltrate psoriatic lesions by detecting CD8α expression. However, CD8α is not only expressed in CD8⁺T cells, but also in NK cells, γδT cells, and dendritic cells (DC). We performed immunofluorescence staining of CD8α with markers for T cells, dendritic cells, and NK cells. The results showed that CD8α co-expressed with CD3 and TCRα, but not with TCRδ, CD11c, or CD56 (Fig. S1 and 1A), which suggested that CD8⁺T cells, and not γδT cells, DC, or NK cells, infiltrated psoriatic lesions.

To investigate the subset of CD8⁺T cells in psoriatic lesions, we detected CD8α and CD8β expression by immunofluorescence staining. We found that the proportion of CD8αα⁺T cells markedly increased in psoriatic lesions (88.48% ± 7.39%), and infiltrated both the dermis and epidermis. Whereas, in normal skin, we found that CD8αβ⁺T cells were predominantly scattered throughout the derma-epidermal junction (Fig. 1B-1C).

Next, we investigated the frequency of circulating CD8αα⁺T cells in patients with psoriasis using flow cytometry. As shown in Figure 1D, the frequency of CD8αα⁺T cells were comparable in patients with psoriasis and healthy controls (Figure 1E, 6.54% ± 1.81% vs. 5.48% ± 1.04%, P > 0.05). There was no correlation between frequency of psoriatic circulating CD8αα⁺T cells and the PASI score (Fig. 1F, R² = 0.008, P = 0.9). Thus, these data indicated that lesional CD8αα⁺T cells, but not CD8αβ⁺T cells, contribute to pathogenesis of psoriasis.

Epidermal CD8αα⁺T cells exhibit tissue-resident memory T cells (T_RM) phenotypes and dermal CD8αα⁺T cells exhibit effector memory (T_EM) phenotypes in psoriatic lesions

We investigated CD8αα⁺T cell phenotypes in patients with psoriasis using the immunofluorescence assay. We found that approximate 90% of the CD8αα⁺T cells did not express CD45RA and CCR7 in psoriatic lesions. In normal skin, CD8⁺T cells did not express CCR7, but partially expressed CD45RA (Fig. S2A-S2B). CD103 and CD69, identified as tissue-resident memory markers, were expressed in T_RMcells. Notably, we found that more than 95% of the CD8αα⁺T cells expressed CD103 in the epidermis of patients with psoriasis, but approximate 1.7% of the CD8αα⁺T cells expressed CD103 in the dermis (Fig. 2A-2B). Unexpectedly, different from CD103 expression, approximate 17.2% of the CD8αα⁺T cells expressed CD69 in the epidermis of patients with psoriasis, but approximate 38.3% of the CD8αα⁺T cells expressed CD103 in the dermis (Fig. 2C-2D).

Thus, these results indicate that psoriatic epidermal CD8αα⁺T cells were predominantly T_RMcells which exhibited the CD69^+/-CD103⁺phenotype and psoriatic dermal CD8αα⁺T cells were T_EMcells which exhibited the CD69^+/-CD103^-CCR7^-CD45RA^- phenotype.

CD8αα⁺T cells do not exhibit a regulatory role in psoriasis

CD8αα⁺T cells expressed Treg cell markers and exhibited a regulatory role in intestinal mucosa. To determine whether CD8αα⁺T cells have a suppressive immune function in psoriasis, we detected the expression of Treg cell markers in psoriatic CD8αα⁺T cells. Immunofluorescence showed that CD8αα⁺T cells expressed little CD122, and did not express Foxp3 and CD25 in psoriatic lesions (Fig. 3).

For verification, we used an in vitro lymphocyte co-culture model of CD8αα⁺T cells and CD4⁺T cells. We analyzed the suppressive function of CD8αα⁺T cells by assessing the proliferation of CD4⁺T cells using flow cytometry. We found that CD8αα⁺T cells enhanced the proliferation of CD4⁺T cells in patients with psoriasis but inhibited its proliferation in healthy controls (Fig. 4A-4C). These results suggest that CD8αα⁺T cells exhibit a pro-inflammatory role in psoriasis, but not a suppressive function.

CD8αα⁺T cells exhibit pro-inflammatory activity in psoriasis

To further investigate the mechanism of how CD8αα⁺T cells exhibited a pro-inflammatory function, we detected cytokines produced by CD8αα⁺T cells in psoriasis. We found that CD8αα⁺T cells could produce IL-17A and IFN-γ in lesions of patients with psoriasis but did not express these cytokines in normal skin (Fig. 5A-5B). Additionally, CD8αα⁺T cells from psoriatic peripheral blood produced significantly higher levels of IL-17A and IFN-γ than those from healthy controls (Fig. 5C-5F). Moreover, CD8αα⁺T cells produce higher levels of IL-17A and IFN-γ than CD8αβ⁺T cells, both in peripheral blood of patients with psoriasis and healthy controls. Thus, these results suggest that CD8αα⁺T cells exhibit a pro-inflammatory function by producing IL-17A and IFN-γ in psoriasis.

The current study investigated the function of CD8αα⁺T cells in psoriasis. We found that the proportion of CD8αα⁺T cells were markedly increased in psoriatic lesions. In addition, psoriatic epidermal CD8αα⁺T cells were predominantly CD69^+/-CD103⁺CCR7^-CD45RA^-T_RM cells, whereas psoriatic dermal CD8αα⁺T cells were CD69^+/-CD103^-CCR7^-CD45RA^-T_EM cells. Moreover, CD8αα⁺T cells exhibited a pro-inflammatory role in psoriasis by producing IL-17A and IFN-γ. Therefore, our results indicate that CD8αα⁺T_RM cells contribute to psoriasis by producing pro-inflammatory cytokines.

Previous studies have shown that dense infiltration of CD8⁺T cells are found in the psoriatic lesions. CD8⁺T cells have been identified as a potent source of pro-inflammatory cytokines in psoriasis ^2,12. However, these studies solely identify CD8⁺T cells by detecting CD8α expression. CD8α is not only expressed on T cells, but also on the surface of NK cells, DC and γδT cells. Thus, by performing immunofluorescence, we found that the identity of infiltrating CD8⁺ cells was not NK cells, DC, or γδT cells, but TCRαβ⁺T cells. Furthermore, CD8αα⁺T cells primarily infiltrated psoriatic lesions, and not CD8αβ⁺T cells.

Like a subpopulation of Th cells, according to different kinds of cytokine production, CD8⁺T cells can be divided into Tc1, Tc2, Tc17, and Tc22. Additionally, unlike the CD4 oligomer, CD8 can be expressed as a CD8αα homodimer and CD8αβ heterodimer on the surface of CD8⁺T cells⁶. Although CD8αα andCD8αβ bind similarly to MHC class I molecules, CD8β endows CD8 with coreceptor function. Indeed, CD8αβ, but not CD8αα, associated with TCR/CD3, strengthens pHMC binding, and promotes CD8 association with lipid rafts and p56^lck and hence TCR signaling. CD8αα excluded from lipid rafts, and negatively regulates TCR activation¹³. As we know, CD8αβ expressed on the surface of T cells is also called cytotoxic T cells. However, CD8αα is expressed on T cells, NK cells, DC, and γδT cells. CD8αα⁺T cells were first found to be infiltrating the intestine of mouse, and contributed to the pathogenesis of intestinal diseases associated with infection and inflammation¹¹. Little is known about its role in human bodies. Jia Zhu et.al. found that CD8αα⁺T cells persisted in the genital skin and mucosa at the derma-epidermal junction to exhibit an immune surveillance role in HSV infection¹⁴. Consistent with this study, we found markedly increased number of CD8αα⁺T cells in the lesions of psoriasis, and they have a pro-inflammatory function.

In the mouse model of inflammatory bowel disease, CD8αα⁺T cells were found to play an immunosuppressive role. As mentioned above, CD8αα can negatively regulate TCR activation by interacting with its ligand, TL, which is abundantly expressed by intestinal epithelial cells. Although Foxp3 and CD25 (IL-2 receptor subunit α) were identified as markers of Treg cells, they are not expressed in CD8αα⁺T cells ^9,10. However, in the intestine of mice, CD122 (IL-2/15 receptor subunit β) is found on the surface of CD8αα⁺T cells and is necessary for cell survival. Consistent with previous studies, we found that Foxp3 and CD25 were negatively expressed in CD8αα⁺T cells of patients with psoriasis, and unexpectedly, CD122 was also expressed little.

Furthermore, previous studies have shown the immunoregulatory role of CD8aa⁺T cells in some animal models. Non-obese diabetic (NOD) mice are defective in CD8aa⁺T cell generation ¹⁵. Additionally, transfer of CD8aa⁺T cells can inhibit colitis, induced by the adoptive transfer of CD4 T cells into severe combined immunodeficient (SCID) mice ¹⁶. Unlike CD4⁺Treg cells, the mechanisms underlying the immunosuppressive function of CD8αα⁺T cells were that they recognized pathogenic TCR-derived peptides, which is presented on the MHC-I Qa-1 molecule of pathogenic T cells in an activation-dependent manner^8,17,18.Therefore, to further determine whether CD8αα⁺T cells have an immunosuppressive function in psoriasis, we cocultured CD8αα⁺T cells with auto-CD4⁺T cells. Consistent with previous studies, CD8αα⁺T cells from healthy subjects suppressed the proliferation of auto-CD4⁺T cells, but promoted its proliferation in patients with psoriasis. Thus, our results indicate that CD8αα⁺T cells play a pro-inflammatory role in psoriasis, instead of an immunosuppressive function.

In mice, CD8αα⁺T cells are identified as T_RMcells, which persist in the same sites of intestinal epithelium for a long time, noncirculating and largely maintained independently of circulating populations ¹¹. These T_RMcells are phenotypically heterogeneous, and there are no perfect markers of tissue residency; the most commonly associated markers are CD69 (c-type lectin), CD103 (an E-cadherin receptor), CD49a, CXCR3/6. Additionally, unlike central memory (T_CM) and T_EM cells, T_RM cells do not express CCR7 (a lymph node homing receptor) and CD62L (L-selectin) ^19-21. Previous studies have shown that CD103⁺CD8⁺T_RM cells and CD69⁺CD8⁺T_RM cells infiltrated in psoriatic lesions and non-lesional psoriatic skin; they are even found in the cleared skin after treatment and could produce IL-17, IFN-γ andIL-22 persistently ^22,23. Cheuk et al. reported that CD49a^-CD8⁺T_RM cells from psoriatic lesions predominantly generated the IL-17 response, whereas CD49a⁺CD8⁺T_RM cells preferentially produced IFN-γ, and displayed high cytotoxic capacity contributing to vitiligo²⁴. In our study, we found that more than 95% of the CD8⁺T cells in psoriatic lesions are of the CD8αα⁺phenotype, and identified a new phenotype of T_RM cells, CD103⁺CD8αα⁺, in the epidermis of psoriatic lesions. Additionally, CD103^-CD8αα⁺T cells in the dermis may be not T_RM cells. Although CD69 be considered to be marker of T_RM cells, it can also be expressed in T effector cells instantaneously. We found that CD69 partially expressed both in CD103⁺CD8αα⁺ T_RM cells in epidermis and CD103^-CD8αα⁺T_EM cells in psoriasis lesions. Moreover, CD8αα⁺T cells from both epidermis and dermis do not express CCR7 and CD45RA (a naïve T cell marker) in psoriatic lesions. Thus, our results indicate that CD8αα⁺T cells, as a subset of T_RMcells in epidermis, contribute to the pathogenesis of psoriasis.

However, there are still some limitations in our study. Because it is difficult to obtain enough skin tissue from patients with psoriasis, we just performed immunofluorescence to identify the phenotype of CD8αα⁺ T cells in lesions. Flow cytometry will be better to identify the phenotype of lesional CD8αα⁺ T cells. In addition, although we found CD103⁺CD8αα⁺ T_RM cells infiltrated the epidermis of psoriasis, some of them did not express CD69. Difference of CD69⁺CD103⁺CD8αα⁺T_RM cells from CD69^-CD103⁺CD8αα⁺ T_RM cells should be further investigated.

In conclusion, our results suggested that CD8αα⁺T cells exhibited an immunosuppressive function in healthy controls and exhibited the tissue-resident memory phenotype in psoriatic epidermis, playing a pro-inflammatory role by producing elevated levels of IL-17A and IFN-γ. CD8αα⁺T cells in the dermis may redirect from peripheral blood exhibiting the phenotype of T_EMcells to contribute to the pathogenesis of psoriasis.

Patients and samples

This study was approved by the ethical committee of Xijing Hospital of the Fourth Military Medical University. All healthy volunteers and patients with psoriasis agreed to participate in this study and provided written informed consent. Twenty-milliliter blood samples were collected from each patient in the progressive stage with mild-to-moderate psoriasis (psoriasis area and severity index, PASI≥5), or severe psoriasis (PASI≥12), or who was a healthy control (Supplementary Table S1). Normal skin and psoriatic lesions were obtained from patients via biopsy. All patients were diagnosed clinically and pathologically. Patients did not receive any topical treatment for a minimum of 1 month and were naïve to photo(chemo)therapy or systemic treatments for psoriasis. All patients and controls were otherwise healthy and did not use any other systemic medications.

Immunofluorescence analysis

Immunofluorescence was performed on paraffin-embedded 5-μm sections of skin samples. Following paraffin removal, epitope retrieval, and blocking in phosphate buffered saline/4% bovine serum albumin, sections were incubated with primary antibodies for 16 hours at 4℃. Thereafter, secondary antibodies were added and incubated for 1 hour at room temperature in the dark. Nuclei were stained with Hoechst (Beyotime, Shanghai, China, at a dilution of 1:1000) for 10 minutes at room temperature in the dark. Immunofluorescence staining was analyzed using an OLYMPUS FV10 confocal laser scanning microscope (CLSM) 510 system (Carl Zeiss AB, Jena, Germany). Primary and secondary antibodies are listed in Supplementary Table S2.

Flow cytometry

To detect cytokine production, peripheral blood mononuclear cells (PBMCs) were incubated with lipopolysaccharides for 12 hours to activate monocytes exhibiting antigen presentation, followed by a cell stimulation cocktail (eBioscience, CA, USA) for 4 hours to amplify the immune response and maintain cytokines intracellularly. PBMCs were incubated with anti-human CD3-PE/CY7, anti-human CD8α-PE/CY5 and anti-human CD8β-super bright 436 (eBioscience, CA, USA) at 4℃ for 30 minutes. After fixation and permeabilization using fixation/permeabilization solution and permeabilization buffer (all from eBioscience, CA, USA), cells were incubated with anti-human IL-17A-PE or anti-human IFN-γ-PE at 4℃ for 30 minutes. Then, flow cytometric analysis using FACS Calibur (BD Biosciences, USA). Data were analyzed with the BD FACS Diva software (BD Biosciences). Primary and secondary antibodies are listed in Supplementary Table S2.

T cell isolation and sorting

Peripheral blood mononuclear cells were separated using Ficoll-Hypaque (Dakewei, Shenzhen, China). Cells were labeled with anti-human CD3-PECY7, anti-human CD4-APC, anti-human CD8α-PE, and anti-human CD8β- super bright 436. Thereafter, CD3⁺CD4⁺Tresp cells, CD3⁺CD8α⁺CD8β⁺T cells, and CD3⁺CD8α⁺CD8β^-T cells were purified using fluorescence-activated cell sorting (FACS; Moflo XDP, Beckman, CA, USA) at purity >95%. Isolated cells were subsequently cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS; Gibco, CA, USA).

In vitro function assay of CD8αα⁺T cells

To investigate the suppressive function of CD8αα⁺T cells, FACS-sorted CD4⁺T cells from healthy subjects and patients with psoriasis (5 × 10⁴ per well) were labeled with carboxyfluorescein succinimidyl ester (CFSE), and subsequently cocultured separately with CD8αα⁺T cells (5 × 10⁴ per well) isolated from the same subject in 96-well U-bottom plates. Thereafter, dynabeads human T-activator CD3/CD28 at a bead-to-cell ratio of 1:1 and rIL-2 (3 µg/mL) were added to cocultures and incubated for 96 hours at 37℃. The proliferation of CD4⁺T cells was then analyzed using flow cytometry based on the CFSE dilution.

Statistical analysis

Data analysis was performed using the GraphPad Prism version 7.0 software (GraphPad Software, San Diego, CA). Statistically significant differences between two groups were determined by two-tailed t-tests. P-values of less than 0.05 were considered statistically significant. Data are expressed as the mean standard error.

T_RMcells, tissue-resident memory T cells; T_EM cells, effector memory; IL-17, interleukin-17; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; TCRs, T-cell receptors; MHC, major histocompatibility complex; TL, Thymus leukemia; PASI, psoriasis area and severity index; DC, dendritic cells;

Ethics and consent

We declare that all methods were performed in accordance with relevant guidelines and regulations.

Acknowledgments

This study was funded by National Natural Science Foundation of China (no. 81703113 and 81903207). We thank all the patients with psoriasis and healthy controls for their participation in the study. We thank editage (www.editage.cn) for their linguistic assistance during the preparation of this manuscript.

Author Contributions

Yangyang Zhang, Yiting Lin and Lei Wang performed the research, and analyzed the data and wrote the manuscript; Xiuwen Sun performed the research; Erle Dang and Ke Xue analyzed the data; Weigang Zhang, Qian Zhang, Junqin Li and Kaiming Zhang contribute essential reagents or tools; Gang Wang and Bing Li designed the research study, analyzed the data and wrote the manuscript.

Conflicts of interest

The authors have no potential conflict of interest to declare.

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No competing interests reported.

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Cd8αα+T Cells Exert a Pro-inflammatory Role in Patients With Psoriasis

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