Tissue‐Resident Memory <scp>CD</scp>8+ T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjögren's Syndrome

Gao, Cai; Yao, Yuan; Li, Liang; Yang, Shu; Chu, Hui; Tsuneyama, Koichi; Li, Xiao Mei; Gershwin, M. Eric; Lian, Zhe Xiong

doi:10.1002/art.40676

Cited by 52 publications

(65 citation statements)

References 47 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this study, we focused on CD4 + Th cells, however, the importance of CD8 + T cells in the immunopathology of pSS has been indicated previously in pSS patients and Sjögren‐like disease models . In this respect, the interplay between CCR9 + Th cells and (CCR9+) CD8 T cells has been demonstrated previously to play a key role in immunopathology .…”

Section: Discussionmentioning

confidence: 92%

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

et al. 2019

View full text Add to dashboard Cite

CCR9 + T helper (Th) cells can induce Sjögren‐like symptoms in mice and both CCR9 + Th cells and their ligand CCL25 are increased in the salivary glands of primary Sjögren's syndrome (pSS) patients. Increased circulating CCR9 + Th cells are present in pSS patients. CCR9 + Th cells are hyperresponsive to IL‐7, secrete high levels of IFN‐γ, IL‐21, IL‐17 and IL‐4 and potently stimulate B cells in both patients and healthy individuals. Our aim was to study co‐expression of chemokine receptors on CCR9 + Th cells and whether in pSS this might differentially affect CCR9 + Th cell frequencies. Frequencies of circulating CCR9 + and CCR9‐ Th cells co‐expressing CXCR3, CCR4, CCR6 and CCR10 were studied in pSS patients and healthy controls. CCL25, CXCL10, CCL17, CCL20 and CCL27 mRNA and protein expression of salivary gland tissue of pSS and non‐Sjögren's sicca (non‐SS) patients was assessed. Chemotaxis assays were performed to study migration induced by CXCL10 and CCL25. Higher expression of CXCR3, CCR4 and CCR6 but not CCR10 was observed on CCR9 + Th cells as compared to cells lacking CCR9. Decreased frequencies of circulating memory CCR9 + CXCR3+ Th cells were found in pSS patients, which was most pronounced in the effector memory subset. Increased salivary gland CCL25 and CXCL10 expression significantly correlated and both ligands functioned synergistically based on in vitro induced chemotaxis. Decreased memory CXCR3 + CCR9+ Th cells in blood of pSS patients may be due to a concerted action of overexpressed ligands at the site of inflammation in the salivary glands facilitating their preferential migration and positioning in the lymphocytic infiltrates.

show abstract

Section: Discussionmentioning

confidence: 92%

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Although this study focused on analyzing associations between lymphocytes changes with persistent viral clearance and its relationship with SS etiopathogenesis, it might suggest that altered frequency of circulating CTL might be related to their high infiltration into damaged tissues. In this line, based on HLA-DR+ expression, a high number of activated CD8+ T cells was found infiltrating LSG [ 3 ], and based on CD69 and CD103 expression, CD8+ T cells with a tissue-resident memory phenotype (CD8+TRM cells) were found as dominant infiltrating cells, adjacent to salivary duct epithelial cells [ 9 ].…”

Section: Cytotoxic T Cellsmentioning

confidence: 99%

“…On the other hand, in a murine model of SS disease, infiltrating cytotoxic CD8+ T cells driving pathologic implications has been documented. Activated CD8+ T cell are present in salivary and submandibular glands from mice with the capability to produce high levels of IFN-γ [ 9 , 110 ]. Adoptive transference of CD8+ T cell with cytotoxic phenotype may drive specific inflammation in lacrimal gland in NOD-SCID mice [ 110 ].…”

Section: Cytotoxic T Cellsmentioning

confidence: 99%

“…Adoptive transference of CD8+ T cell with cytotoxic phenotype may drive specific inflammation in lacrimal gland in NOD-SCID mice [ 110 ]. Furthermore, CD8+ T cell-specific depletion abrogates SS features development, and blocking IFN-γ production decreases T cells infiltration [ 9 ].…”

Section: Cytotoxic T Cellsmentioning

confidence: 99%

“…Tfh cells are taking special attention for their essential roles in ectopic lymphoid structures (ELS) development in pSS patients, due to their germinal center (GC)-like organization that allows a potent B cell response [ 8 ]. On the other hand, CTL have also been implicated into SS pathology, since data from a murine SS model and human biopsies reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the SG [ 9 ]. Strikingly, a novel T cells subset is emerging, namely a kind of regulatory T cell localized in the GC to limit the humoral response, called follicular regulatory T cells (Tfr), which might play a critical protective role, since their deficiency affects the salivary glands with lymphocyte infiltration and antibody deposition in a mouse experimental model of SS [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

2020

View full text Add to dashboard Cite

Sjogren’s syndrome (SS) is an autoimmune disease whose pathogenesis is characterized by an exacerbated T cell infiltration in exocrine glands, markedly associated to the inflammatory and detrimental features as well as the disease progression. Several helper T cell subsets sequentially converge at different stages of the ailment, becoming involved in specific pathologic roles. Initially, their activated phenotype endows them with high migratory properties and increased pro-inflammatory cytokine secretion in target tissues. Later, the accumulation of immunomodulatory T cells-derived factors, such as IL-17, IFN-γ, or IL-21, preserve the inflammatory environment. These effects favor strong B cell activation, instigating an extrafollicular antibody response in ectopic lymphoid structures mediated by T follicular helper cells (Tfh) and leading to disease progression. Additionally, the memory effector phenotype of CD8+ T cells present in SS patients suggests that the presence of auto-antigen restricted CD8+ T cells might trigger time-dependent and specific immune responses. Regarding the protective roles of traditional regulatory T cells (Treg), uncertain evidence shows decrease or invariable numbers of circulating and infiltrating cells. Nevertheless, an emerging Treg subset named follicular regulatory T cells (Tfr) seems to play a critical protective role owing to their deficiency that enhances SS development. In this review, the authors summarize the current knowledge of T cells subsets contribution to the SS immunopathology, focusing on the cellular and biomolecular properties allowing them to infiltrate and to harm target tissues, and that simultaneously make them key therapeutic targets for SS treatment.

show abstract

NK1.1⁺ innate lymphoid cells in salivary glands inhibit establishment of tissue‐resident memory CD8⁺ T cells in mice

et al. 2020

View full text Add to dashboard Cite

NK1.1 + cells found in salivary glands (SG) represent a unique cell population of innate lymphoid cells (ILC) with characteristics of both conventional NK cells and ILC1. Here, we demonstrate that these NK1.1 + cells limit the accumulation and differentiation of virus-specific tissue-resident memory CD8 + T cells (T RM cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV-specific CD8 + T RM cells by NK1.1 + cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46 iCre+ Eomes fl/fl mice revealed that Eomes-dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of T RM cells by tissue-resident ILC may be particularly important to prevent immunopathology in this organ.

show abstract

Tissue‐Resident Memory CD8+ T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjögren's Syndrome

Abstract: These data reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD8+ T cells may be a rational therapy for the management of SS in human subjects.

Cited by 52 publications

References 47 publications

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

NK1.1⁺ innate lymphoid cells in salivary glands inhibit establishment of tissue‐resident memory CD8⁺ T cells in mice

Contact Info

Product

Resources

About

Tissue‐Resident Memory CD8+ T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjögren's Syndrome

Abstract: These data reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD8+ T cells may be a rational therapy for the management of SS in human subjects.

Cited by 52 publications

References 47 publications

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

NK1.1+ innate lymphoid cells in salivary glands inhibit establishment of tissue‐resident memory CD8+ T cells in mice

Contact Info

Product

Resources

About

NK1.1⁺ innate lymphoid cells in salivary glands inhibit establishment of tissue‐resident memory CD8⁺ T cells in mice