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The Role of ICOS in Peripheral Inflammation in Lupus
Author(s) -
Eardley Leah Diane,
Odegard Jared,
Craft Joseph
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.668.18
Subject(s) - lupus nephritis , cxcr3 , systemic lupus erythematosus , chemokine , immunology , inflammation , chemokine receptor , c c chemokine receptor type 6 , kidney , medicine , biology , endocrinology , disease
T and B cells, dendritic cells (DC) and macrophages infiltrate the kidneys of lupus‐prone mice, with analogous infiltrates found in humans with lupus nephritis. These cells, as well as circulating autoantibodies, can produce severe renal disease in lupus. We are interested in the role of CD4+ T cells in promoting such inflammation. We have also utilized the costimulatory molecule ICOS to investigate the mechanisms by which CD4+ T cells contribute to peripheral inflammation in lupus. Our lab and others have demonstrated that the costimulatory molecule ICOS is necessary for cellular infiltration into the kidneys of MRL/ Fas lpr mice, a murine model of lupus. ICOS−/− MRL/ Fas lpr mice have greatly reduced renal cellular infiltrates. The infiltrates of kidneys were characterized by FACS, immunofluorescence, and histology. ICOS is expressed on the majority of CD4+ T cells found in the kidney. Ex vivo stimulated ICOS−/− CD4+ T cells from MRL/ Fas lpr mice produce significantly less quantities of effector cytokines, such as IFNγ, TNFα, IL‐10, and IL‐5, compared to ICOS+/+ CD4+ T cells from MRL/Faslpr mice. However, similar levels of certain chemokines, including MIG, are found in ICOS−/− MRL/ Fas lpr kidneys, compared to ICOS+/+ MRL/ Fas lpr kidneys. In addition, ICOS+/+ and ICOS−/− MRL/ Fas lpr CD4+ T cells expressed similar amounts of some chemokine receptors (CXCR3, the receptor for MIG), but altered amounts of other chemokine receptors (CCR6). Although the implications for CD4+ expression of CCR6 is unclear, as less than 10% of kidney infiltrating CD4+ T cells express CCR6. Taken together, these data demonstrate ICOS dependent and independent cytokine and chemokine production in lupus mice, as well as chemokine receptor expression by CD4+ T cells in MRL/ Fas lpr mice.