The Role of ICOS in Peripheral Inflammation in Lupus

Abstract

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/Faslpr mice, a murine model of lupus. ICOS−/− MRL/Faslpr 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/Faslpr 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/Faslpr kidneys, compared to ICOS+/+ MRL/Faslpr kidneys. In addition, ICOS+/+ and ICOS−/− MRL/Faslpr 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/Faslpr mice.