IL-7R low memory CD8+ T cells are significantly elevated in patients with systemic lupus erythematosus

Kim, Jung-Sik; Cho, Bon A.; Sim, Ji Hyun; Shah, Kamini; Woo, Connie M.; Lee, Eun Bong; Lee, Dong Sup; Kang, Jae Seung; Lee, Wang Jae; Park, Chung Gyu; Craft, Joe; Kang, Insoo; Kim, Hang Rae

doi:10.1093/rheumatology/kes100

Cited by 25 publications

(22 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inhibiting fractalkine or CX3CR1 reduced disease activity in mouse models of RA, SLE and atherosclerosis (52–54). The expansion of IL-7Rα low EM CD8 + T cells and increased expression of CX3CR1 on CD8 + T cells were reported in the peripheral blood of patients with SLE and RA, respectively (16, 51). These observations warrant further studies investigating the specific role of CX3CR1 expression by CD8 + T cells in inflammatory diseases.…”

Section: Discussionmentioning

confidence: 96%

“…The differential expression of IL-7Rα by EM CD8 + T cells was associated with different levels of DNA methylation in the IL7RA gene promoter (15). Expansion of the IL-7Rα low EM CD8 + T cells was found in older adults and patients with systemic lupus erythematosus (SLE), suggesting a potential association of this cell subset with immunosenescence and inflammation (14, 16). However, the exact functional characteristics of IL-7Rα low and high EM CD8 + T cells and the mechanism(s) defining such characteristics are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine

Shin

You

Kang

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

DNA methylation is an epigenetic mechanism that modulates gene expression in mammalian cells including T cells. Memory T cells are heterogeneous populations. Human effector memory (EM) CD8+ T cells in peripheral blood contain two cell subsets with distinct traits that express low and high levels of the IL-7 receptor alpha chain (IL-7Rα). However, epigenetic mechanisms involved in defining such cellular traits are largely unknown. Here we employ genome-wide DNA methylation and individual gene expression to show the possible role of DNA methylation in conferring distinct traits of chemotaxis and inflammatory responses in human IL-7Rαlow and high EM CD8+ T cells. In particular, IL-7Rαlow EM CD8+ T cells had increased expression of CX3C receptor 1 (CX3CR1) along with decreased DNA methylation in the CX3CR1 gene promoter compared to IL-7Rαhigh EM CD8+ T cells. Altering the DNA methylation status of the CX3CR1 gene promoter changed its activity and gene expression. IL-7Rαlow EM CD8+ T cells had an increased migratory capacity to the CX3CR1 ligand fractalkine compared to IL-7Rαhigh EM CD8+ T cells, suggesting an important biological outcome of the differential expression of CX3CR1. Moreover, IL-7Rαlow EM CD8+ T cells induced fractalkine expression on endothelial cells by producing IFN-γ and TNF-α, forming an autocrine amplification loop. Overall, our study shows the role of DNA methylation in generating unique cellular traits in human IL-7Rαlow and high EM CD8+ T cells, including differential expression of CX3CR1, as well as potential biological implications of this differential expression.

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine

Shin

You

Kang

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Kim et al assessed the expression of SLAMF4 in a CD8+ T cell subpopulation defined as CCR7− IL‐7Rα low and observed that it was increased in SLE patients . They did not distinguish the CD45RA+ effector memory and CD45RA− terminally differentiated effector memory populations among the CD8+ CCR7− T cells.…”

Section: Discussionmentioning

confidence: 99%

“…The percentages of SLAMF4‐expressing NK cells and monocytes are reduced in patients with SLE compared with healthy controls . In addition, Kim et al reported that the frequency of interleukin‐7 receptor α‐chain (IL‐7Rα) low effector memory CD8+ T cells was increased in patients with SLE and that these cells had higher levels of SLAMF4 expression compared with IL‐7Rα high effector memory CD8+ T cells . Therefore, engagement of SLAMF4 enhanced the cytotoxic function of IL‐7Rα low effector memory CD8+ T cells against target cells.…”

mentioning

confidence: 99%

Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4–Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus

Kis-Tóth

Comte

Karampetsou

et al. 2015

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4, CD244, 2B4) by its ligand SLAMF2 (CD48) modulates function and expansion of both NK cells and a subset of cytotoxic CD8+ T cells. As the cytotoxicity of CD8+ T lymphocytes isolated from systemic lupus erythematosus (SLE) patients is known to be impaired, we assess here whether expression and function of the checkpoint regulator SLAMF4 is altered on SLE CD8+ T cells. Methods Expression of SLAMF4 by healthy and SLE T cells was determined by Q-PCR and flow cytometry. T cells were activated with anti-CD3 antibody and degranulation activity was monitored by the surface expression of LAMP-1 (CD107a). The SLAMF4+ and SLAMF4− CD8 T cell subpopulations were characterized by LAMP-1, perforin and granzyme B expression and viral peptide-induced proliferation. Results SLAMF4 gene and surface protein expression is downregulated in CD8+ T cells from SLE patients as compared to cells obtained from healthy donors. Importantly, SLE patients have significantly fewer SLAMF4+ CD8+ T cells compared to healthy subjects. SLAMF4− CD8+ T cells from SLE patients have a decreased cytotoxic capacity and proliferative responses to viral peptides. The loss of memory SLAMF4+ CD8+ T cells in SLE patients is linked to the fact that they lose CD8 expression and become double negative T cells. Conclusion A selective loss of SLAMF4+ CD8+ T cells contributes to the compromised ability of SLE T cells to fight against infections.

show abstract

“…Surprisingly, the Class I-MHC–peptide complex on the target cell can regulate the level of expression of SLAMF4 on virus specific cytotoxic T cells by an internalization mechanism 28 . Functional involvement on the surface of human CD8 + T cells is further indicated by the finding that in patients with systemic lupus erythomatosis the number of SLAMF4 + CD8 cells is dramatically increased suggesting that exhausted memory CD8 + cells partake in this complex autoimmune disease states 30–32 . Because functional single nucleotide polymorphism of the human Slamf4 gene are related to the onset of SLE and rheumatoid arthritis 30–32 , the data suggest that variations in Slamf4 gene may affect human inflammatory bowel diseases.…”

Section: Discussionmentioning

confidence: 99%

SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine

et al. 2015

View full text Add to dashboard Cite

Background & Aims Intra-epithelial T cells (IEL) are the first immune cells to respond to pathogens; they help maintain the integrity of the epithelial barrier. We studied the function of the glycoprotein SLAMF4 (encoded by CD244) on the surface of CD8αβ αβ T-cell receptor (TCR)+ IELs, and the roles of these cells in homeostasis of the small intestine in mice. Methods SLAMF4− CD8+ αβTCR+ cells isolated from spleens of OT-I Rag1−/− mice were induced to express gut-homing receptors and transferred to C57BL/6J mice; levels of SLAMF4 cells were measured in small intestine tissues. After administration of anti-CD3 or antigen, with or without anti-SLAM4, to C57BL/6J and Slamf4−/− mice, CD8αβ αβTCR+ IELs were collected; cytokine production and cytotoxicity were measured. Depletion of CX3CR1+ phagocytes was assessed in mice by live-cell confocal imaging or by cytofluorometry; small intestine tissues were analyzed by histology and inflammation was quantified. Results Splenic CD8+ αβTCR+ cells began to express SLAMF4 only after migrating to the small intestine. Injection of C57BL/6J mice with anti-SLAMF4 and anti-CD3 increased levels of interleukin-10 and interferon-γ secretion by IEL, compared injection of only anti-CD3. Similarly, the number of granzyme B+ cytotoxic CD8+ αβTCR+ IELs increased in Slamf4−/− mice following injection of anti-CD3 and anti-SLAMF4, administration of antigen, or injection of anti-CD3. Surprisingly, in vivo activation of CD8αβ+ IELs with anti-CD3 or antigen caused transient depletion of CX3CR1+ phagocytes, which was prolonged by co-injection with anti-SLAMF4 or in Slamf4−/− mice. Anti-CD3 aggravated inflammation in the small intestines of Slamf4−/− mice and Eat2a−/− Eat2b−/− mice, indicated by flattened villi and crypt hyperplasia. Conclusions In mice, the intestinal environment induces SLAMF4 expression and localization to the surface of CD8+ αβTCR+ IELs. Signaling via SLAMF4 controls expansion of cytotoxic CD8αβ+ IELs, which regulate the reversible depletion of lamina propria phagocytes and inflammation in the small intestine.

show abstract

IL-7R low memory CD8+ T cells are significantly elevated in patients with systemic lupus erythematosus

Abstract: Our findings show that SLE patients have increased IL-7Rα(low) EM CD8(+) T cells, possibly contributing to tissue damage through 2B4-mediated cytotoxicity.

Cited by 25 publications

References 39 publications

DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine

DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine

Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4–Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus

SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine

Contact Info

Product

Resources

About