Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis

Couzi, Lionel; Merville, Pierre; Déminière, C.; Moreau, Jean-François; Combe, Christian; Pellegrin, Jean‐Luc; Viallard, Jean‐François; Blanco, Patrick

doi:10.1002/art.22654

Cited by 121 publications

(96 citation statements)

References 30 publications

(32 reference statements)

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“…This is supported by the presence of CD8 + T cells in the periglomerular infiltrate of lupus nephritis patients (38) and by reports that the transfer of CD8 effector cells can induce glomerular damage via IFN-g production in a mouse model of lupus nephritis (39). In our study, we observed an increase in terminally differentiated CD8 + T cells even in lupus nephritis patients that were in remission and/or under mycophenolate mofetil treatment (data not shown).…”

Section: Cd8supporting

confidence: 85%

A Systemic Lupus Erythematosus Endophenotype Characterized by Increased CD8 Cytotoxic Signature Associates with Renal Involvement

et al. 2017

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Systemic lupus erythematosus (SLE) is a highly heterogeneous disease with limited therapeutic options, where clinical manifestations are the result of activation of innate and adaptive immune mechanisms. The elucidation of these mechanisms is critical for identifying novel therapeutic targets and agents that are more likely to benefit individual patients. In this study we investigated the role that CD8+ T cells play in SLE. We studied CD8+ T cell activity in two different cohorts of SLE patients under standard of care (n = 65 total). The analyses included phenotyping of T cell differentiation, intracellular cytokine staining, and whole blood gene expression. We identified a subset of SLE patients (between 30 and 45%) with elevated numbers of terminally differentiated CD8+ T cells, identified as CCR7−CD45RAint-hiCD28−. We refer to this phenotype as cytotoxic, as it is accompanied by an increase in perforin and granzyme B expression and is correlated with a whole blood gene module of cytotoxic activity (p < 5 × 10−9). Consistent with the potential for tissue damage, this cytotoxic phenotype associates with lupus nephritis (p < 0.02). We have identified an SLE endophenotype, characterized by the increase in terminally differentiated CD8+ T cells that correlated with cytotoxic signature and renal manifestations of the disease. These findings suggest that this subgroup of SLE patients may benefit specifically from therapies that block CD8+ T cell activation and differentiation.

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Section: Cd8supporting

confidence: 85%

A Systemic Lupus Erythematosus Endophenotype Characterized by Increased CD8 Cytotoxic Signature Associates with Renal Involvement

et al. 2017

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“…Heymann et al (11) showed that glomerular Ag-specific CTLs induce renal immunopathology with the help of CD4 T cells. Such cooperation between CD8 and CD4 cells is indeed likely and may also explain several somewhat contradictory reports describing the contributions of CD8 and/or CD4 T cells to the pathogenesis of immune glomerular disease (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In a previous study of experimentally induced SLE, we found that both Ag cross-presentation and CD4 T cell help were essential for generating effector CD8 CTLs, leading to glomerular injury (26).…”

Section: Discussionmentioning

confidence: 81%

“…D'Agati et al (20) showed that CD8, rather than CD4, T cells predominate in most of the biopsied kidney samples from patients with SLE. Couzi et al (21) showed that CD8 T cells predominantly infiltrate to the periglomerular region of lupus kidney and are significantly associated with the prognosis of lupus nephritis. Together, these findings reinforce the importance of CD8 T cells in the pathogenesis of lupus nephritis.…”

mentioning

confidence: 99%

IFN-γ–Producing Effector CD8 T Lymphocytes Cause Immune Glomerular Injury by Recognizing Antigen Presented as Immune Complex on Target Tissue

Tsumiyama

Hashiramoto

Takimoto

et al. 2013

The Journal of Immunology

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We investigated the role of effector CD8 T cells in the pathogenesis of immune glomerular injury. BALB/c mice are not prone to autoimmune disease, but after 12 immunizations with OVA they developed a variety of autoantibodies and glomerulonephritis accompanied by immune complex (IC) deposition. In these mice, IFN-γ–producing effector CD8 T cells were significantly increased concomitantly with glomerulonephritis. In contrast, after 12 immunizations with keyhole limpet hemocyanin, although autoantibodies appeared, IFN-γ–producing effector CD8 T cells did not develop, and glomerular injury was not induced. In β2-microglobulin–deficient mice lacking CD8 T cells, glomerular injury was not induced after 12 immunizations with OVA, despite massive deposition of IC in the glomeruli. In mice containing a targeted disruption of the exon encoding the membrane-spanning region of the Ig μ-chain (μMT mice), 12 immunizations with OVA induced IFN-γ–producing effector CD8 T cells but not IC deposition or glomerular injury. When CD8 T cells from mice immunized 12 times with OVA were transferred into naive recipients, glomerular injury could be induced, but only when a single injection of OVA was also given simultaneously. Importantly, injection of OVA could be replaced by one injection of the sera from mice that had been fully immunized with OVA. This indicates that deposition of IC is required for effector CD8 T cells to cause immune tissue injury. Thus, in a mouse model of systemic lupus erythematosus, glomerular injury is caused by effector CD8 T cells that recognize Ag presented as IC on the target renal tissue.

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“…In nephrotoxic nephritis, a model of human crescentic GN, Th type 1 cells specific for a planted glomerular antigen stimulated renal macrophages (27) that caused kidney damage (12). Also CD8 + T cells (CTLs), whose main function is the defense against intracellular pathogens and tumors, are found in periglomerular infiltrates, e.g., in lupus nephritis (7). Several animal models exist for studying CTLs specific to tubular antigen, and these have facilitated elucidating immune mechanisms in interstitial nephritis (29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury

Heymann¹,

et al. 2009

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The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8 + CTLs and CD4 + Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen-specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease.

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Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis

Cited by 121 publications

References 30 publications

A Systemic Lupus Erythematosus Endophenotype Characterized by Increased CD8 Cytotoxic Signature Associates with Renal Involvement

A Systemic Lupus Erythematosus Endophenotype Characterized by Increased CD8 Cytotoxic Signature Associates with Renal Involvement

IFN-γ–Producing Effector CD8 T Lymphocytes Cause Immune Glomerular Injury by Recognizing Antigen Presented as Immune Complex on Target Tissue

Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury

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