Major Histocompatibility Complex Class II Expression by Intrinsic Renal Cells Is Required for Crescentic Glomerulonephritis

The requirement for major histocompatibility complex class II (MHC II) to initiate immune renal injury was studied in a murine model of CD4+ T cell–dependent crescentic glomerulonephritis (GN). C57BL/6 (MHC II+/+) mice developed crescentic GN with glomerular CD4+ T cell infiltration and renal injury, in response to a nephritogenic antigen (sheep globulin) planted on their glomerular basement membrane. MHC II–deficient C57BL/6 mice (MHC II−/−) did not develop crescentic GN, CD4+ T cell infiltration, or injury, indicating that this form of immune glomerular injury is MHC II dependent. The requirement for MHC II expression by intrinsic renal cells was studied in chimeric mice, which expressed MHC II on bone marrow–derived cells and in the thymus, but not in the kidneys. These chimeric mice had normal T and B cell populations and MHC II expression in their spleens and lymph nodes and developed an immune response to systemically and cutaneously administered sheep globulin. However, they did not develop crescentic GN, CD4+ T cell infiltration, or renal injury in response to the sheep globulin planted in their glomeruli. These studies demonstrate that interaction of CD4+ T cells with intrinsic renal cells expressing MHC II is required for development of cell-mediated immune renal injury.

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Interleukin-12 from Intrinsic Cells Is an Effector of Renal Injury in Crescentic Glomerulonephritis

Journal of the American Society of Nephrology ◽

10.1681/asn.v123464 ◽

2001 ◽

Vol 12 (3) ◽

pp. 464-471 ◽

Cited By ~ 2

Author(s):

JENNIFER R. TIMOSHANKO ◽

A. RICHARD KITCHING ◽

STEPHEN R. HOLDSWORTH ◽

PETER G. TIPPING

Keyword(s):

Bone Marrow ◽

T Cell ◽

Renal Injury ◽

Crescentic Glomerulonephritis ◽

Delayed Type Hypersensitivity ◽

Interleukin 12 ◽

Renal Cells ◽

Chimeric Mice ◽

Crescent Formation

Abstract. Interleukin-12 (IL-12) directs the cognate nephritogenic T helper type 1 responses that initiate renal injury in murine crescentic glomerulonephritis (GN). The recent demonstration of IL-12 production by intrinsic renal cells, including mesangial and proximal tubular cells, raises the possibility that IL-12 from nonimmune cells may contribute to inflammatory renal injury. To address this possibility, the development of sheep anti-mouse glomerular basement membrane globulin—induced crescentic GN was studied in C57BL/6 wild-type (WT), IL-12—deficient (IL-12 -/-), and IL-12 “chimeric” mice. IL-12 chimeric mice were produced by transplantation of WT bone marrow into IL-12 -/- mice to restore IL-12 production by immune cells, while leaving them deficient in renal IL-12 production. WT and “sham” chimeric mice (normal bone marrow transplanted into WT mice) developed crescentic GN with glomerular T-cell and macrophage recruitment and impaired renal function (elevated proteinuria and serum creatinine) 10 d after initiation of GN. IL-12 -/- mice showed significant protection from GN. Chimeric IL-12 mice showed significant attenuation of crescent formation, glomerular T-cell and macrophage accumulation, and renal impairment, compared with WT and sham chimeric mice, but were not protected to the same extent as IL-12 -/- mice. IL-12 chimeric mice showed no attenuation of their systemic cognate immune response to the nephritogenic antigen (sheep globulin), indicated by antigen-specific circulating antibody and cutaneous delayed-type hypersensitivity. These studies indicate that IL-12 produced by non—bone marrow derived intrinsic renal cells contributes to immune renal injury. They provide the first in vivo demonstration of a proinflammatory role for an intrinsic renal cell—derived cytokine in renal inflammation.

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Abstract 4303: Heme Oxygenase 1 Expression in Dendritic Cells Drives Cd4+ T Cell Activation in Transplantation Atherosclerosis

Circulation ◽

10.1161/circ.118.suppl_18.s_863 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Annemarie M Noordeloos ◽

C Cheng ◽

E van Deel ◽

D Tempel ◽

M L Simoons ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Heme Oxygenase 1 ◽

Cell Ratio ◽

Mhc Ii ◽

T Cell Infiltration ◽

T Cell Priming

Although over-expression of heme oxygenase-1 (HO-1) attenuates transplantation arteriosclerosis, the mechanism by which HO-1 exerts its protective effect remains unclear. In order to investigate the effect of HO-1 expression specifically in the dendritic cell (DC) in the context of transplantation atherosclerosis, we studied the effect of HO1-deficient versus wildtype (WT) DCs on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. At day 0 C57bl6 mice received either WT (N=7) or HO1-knockout DCs (N=7) pre-sensitized with Balb/c splenocytes lysate. At day 10 an allogenic aorta segment derived from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice. 14 days post transplantation, the grafts were harvested and analyzed by imumnohistology. Adoptive transfer of HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 versus 38428 μm2 P<0.05). HO-1 deficient DCs also increased medial thickeness (15936 versus 12034 μm2 P<0.05), reduced intimal VSMCs content (46 versus 75% P<0.05) and resulted in more prominent medial cell infiltration (461 versus 232 μm2 P<0.05). In the transplanted aorta of the with HO-1 nullizygous DCs treated recipient group, an increase in CD4+ T-cell infiltration (9.5 versus 0.2% in WT P<0.05) and IgG deposition, concomitant to a decrease of CD8+ T cell infiltration (8.1 versus 14.3%, P<0.05) was observed. In line with these observations, in vitro analysis of HO-1 deficiency in DC function showed an increased priming potential for CD4+ T cells, thereby increasing the CD4+/CD8+ T cell ratio. Increased efficiency in CD4+ T cell priming by HO-1 deficient DCs was facilitated by a higher cell surface level of MHC II. Further studies indicated that HO-1 deficiency increased STAT1 phosphorylation, thereby enhancing CIITA gene expression that lead to increased MHC II levels on the DCs cell surface. HO-1 deficiency in dendritic cells increases vascular cell infiltration with a higher CD4+/CD8 T-cell ratio in vascular allografts resulting in an augmented form of transplantation arteriosclerosis. This effect is facilitated by a STAT1-CIITA-MHCII dependent intracellular pathway.

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Abstract 760: Heme Oxygenase-1 expression in Dendritic Cells determines the Outcome of Transplantation Arteriosclerosis

Circulation ◽

10.1161/circ.116.suppl_16.ii_146 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Annemarie Noordeloos ◽

Elza van Deel ◽

Denise Hermes ◽

Maarten L Simoons ◽

Dirk J Duncker ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Heme Oxygenase ◽

T Cell Activation ◽

Neointimal Hyperplasia ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Heme Oxygenase 1 ◽

T Cell Infiltration ◽

Mhcii Expression

Introduction: Although expression of heme oxygenase-1 (HO1) attenuates transplantation arteriosclerosis, the mechanism by which HO1 exerts its protective effect remains unclear. We studied the effect of HO1-deficient vs. wildtype (WT) dendritic cells (DCs) on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. Methods: At day 0 C57bl6 mice received either WT (n=6) or HO1-knockout DCs (n=6) pre-sensitized with Balb/c splenocytes lysate to accelerate the development of arteriosclerosis. At day 10 an aorta segment from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice.14 days after transplantation allografts were excised and processed for immunohistochemical analysis. Results: HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 vs. 46114μm 2 P<0.05) and incidence of intima formation (83 vs. 50% in WT DC). HO1 deficient DCs also increased medial thickeness (15936 vs.12034 μm 2 P<0.05) and intimal VSMCs content (76 vs. 46% P<0.05) and resulted in more prominent medial cell infiltration (461μm 2 vs. 232μm 2 P<0.05). Although HO1 deficient and WT DCs could be detected in allografts, HO1-nullizygous DCs induced an increase in CD4+ T-cell infiltration (9.5 vs. 0.1% in WT P<0.05) concomitant to a decrease of CD8+ T cell infiltration (8 vs.14%, P<0.05). In line with these observations Affymetrix microarray analysis confirmed that HO1 deletion in DCs was associated with a significant downregulation of MHCII-H2A expression (associated with CD4+T-cell activation) and induction of inhibitors of MHCII expression (including IK protein) whereas MHC I expression remained unchanged. Conclusions: HO1 expression in dendritic cells increases vascular cell infiltration with a higher CD8+/CD4+ T-cell ratio by stabilizing MHCII expression in vascular allografts resulting in inhibition of neointima formation and hence improved allograft survival.

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Both Stat5a and Stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue

Blood ◽

10.1182/blood.v95.4.1370.004k29_1370_1377 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1370-1377 ◽

Cited By ~ 63

Author(s):

Shin-ichiro Kagami ◽

Hiroshi Nakajima ◽

Kotaro Kumano ◽

Kotaro Suzuki ◽

Akira Suto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Specific Ige ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Cell Recruitment ◽

Eosinophil Recruitment ◽

Airway Eosinophilia ◽

T Cell Infiltration

Antigen-induced eosinophil recruitment into the airways of sensitized mice is mediated by CD4+ T cells and their cytokines, especially IL-5. In this study, we found that the antigen-induced airway eosinophilia was diminished in Stat5a-deficient (Stat5a−/−) mice and Stat5b-deficient (Stat5b−/−) mice. We also found that antigen-induced CD4+ T-cell infiltration and IL-5 production in the airways were diminished in Stat5a−/− mice and Stat5b−/− mice. Moreover, antigen-induced proliferation of splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice, suggesting that the generation of antigen-primed T cells may be compromised in Stat5a−/−mice and Stat5b−/− mice and this defect may account for the diminished antigen-induced T-cell infiltration into the airways. Interestingly, IL-4 and IL-5 production from anti-CD3–stimulated splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice. However, antigen-specific IgE and IgG1 production was diminished in Stat5a−/− mice but not in Stat5b−/− mice, whereas antigen-specific IgG2a production was increased in Stat5a−/− mice, suggesting the enhanced Th1 responses in Stat5a−/− mice. Finally, we found that eosinophilopoiesis induced by the administration of recombinant IL-5 was also diminished in Stat5a−/− mice and Stat5b−/− mice. Together, these results indicate that both Stat5a and Stat5b are essential for induction of antigen-induced eosinophil recruitment into the airways and that the defects in antigen-induced eosinophil recruitment in Stat5a−/− mice and Stat5b−/− mice result from both impaired IL-5 production in the airways and diminished IL-5 responsiveness of eosinophils.

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Anti-IL-16 therapy reduces CD4+ T-cell infiltration and improves paralysis and histopathology of relapsing EAE

Journal of Neuroscience Research ◽

10.1002/jnr.20377 ◽

2005 ◽

Vol 79 (5) ◽

pp. 680-693 ◽

Cited By ~ 27

Author(s):

Dusanka S. Skundric ◽

Rujuan Dai ◽

Vaagn L. Zakarian ◽

Denise Bessert ◽

Robert P. Skoff ◽

...

Keyword(s):

T Cell ◽

Cd4 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration

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Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment.

Journal of Experimental Medicine ◽

10.1084/jem.184.4.1573 ◽

1996 ◽

Vol 184 (4) ◽

pp. 1573-1578 ◽

Cited By ~ 11

Author(s):

R Schulz ◽

A L Mellor

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Lymphoid Cells ◽

Cd4 T Cell ◽

Cell Compartment ◽

Mhc I ◽

Mhc Ii ◽

Histocompatibility Complex ◽

Self Peptides

Transgenic mice expressing self major histocompatibility complex (MHC) class I (H-2Kb) antigen solely in lymphoid cell lineages do not acquire tolerance to H-2Kb expressed on skin grafts. H-2Kb-specific cytotoxic T cell responses were completely abrogated in these mice, even after they had rejected skin grafts. Moreover, thymocytes expressing T cell receptors that confer H-2Kb reactivity on cytotoxic CD8+ T cells were eliminated. The ability to reject grafts correlated with the presence of a novel population of H-2Kb-reactive CD4+ T cells. At least some of these CD4+ T cells recognize peptides derived from H-2Kb by processing. We conclude that self MHC I antigens induce tolerance in the CD8 T cell compartment via negative selection when expressed exclusively by lymphoid cells. In contrast, tolerance to MHC class II-restricted self peptides derived by processing of such MHC I antigens is not induced in the CD4 T cell compartment. This suggests that effective transfer of self antigens from lymphoid cells to MHC II-positive cells that can process and present them as self peptides to thymocytes or CD4+ T cells does not take place in vivo. Thus, sequestration of self antigens and MHC II molecules in distinct cell types in the thymic microenvironment allows potentially autoreactive and functionally competent CD4+ T cells that recognize cryptic MHC II-restricted self peptides to mature into the peripheral T cell repertoire under normal physiological circumstances.

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The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis

Clinical & Experimental Immunology ◽

10.1093/cei/uxab023 ◽

2021 ◽

Author(s):

Xueyuan Yu ◽

Jiajia Lv ◽

Jun Wu ◽

Yong Chen ◽

Fei Chen ◽

...

Keyword(s):

T Cell ◽

Mouse Brain ◽

Autoimmune Encephalitis ◽

Cell Number ◽

Janus Kinase ◽

Cd4 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration ◽

The Brain ◽

Nlrp3 Expression

Abstract NLRP3 inflammasome hyperactivation contributes to neuroinflammation in autoimmune disorders, but the underlying regulatory mechanism remains to be elucidated. We demonstrate that compared with wild-type (WT) mice, mice lacking thymic stromal lymphopoietin (TSLP) receptor (TSLPR) (Tslpr -/- mice) exhibit a significantly decreased experimental autoimmune encephalitis (EAE) score, reduced CD4 + T cell infiltration, and restored myelin basic protein (MBP) expression in the brain after EAE induction by myelin oligodendrocyte glycoprotein35-55 (MOG35-55). TSLPR signals through Janus kinase (JAK)2, but not JAK1 or JAK3, to induce NLRP3 expression, and Tslpr -/- mice with EAE show decreased JAK2 phosphorylation and NLRP3 expression in the brain. JAK2 inhibition by ruxolitinib mimicked loss of TSLPR function in vivo and further decreased TSLP expression in the EAE mouse brain. The NLRP3 inhibitor MCC950 decreased CD4 + T cell infiltration, restored MBP expression, and decreased IL-1β and TSLP levels, verifying the proinflammatory role of NLRP3. In vitro experiments using BV-2murine microglia revealed that TSLP directly induced NLRP3 expression, phosphorylation of JAK2 but not JAK1orJAK3, and IL-1β release, which were markedly inhibited by ruxolitinib. Furthermore, EAE induction led to an increase in the Th17 cell number, a decrease in the regulatory T (Treg) cell number in the blood, and an increase in the expression of the cytokine IL-17A in the WT mouse brain, which was drastically reversed in Tslpr -/- mice. In addition, ruxolitinib suppressed the increase in IL-17A expression in the EAE mouse brain. These findings identify TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders.

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