Activated CD4+ T cells target mesangial antigens and initiate glomerulonephritis.

Abstract

Aims: The role of kidney infiltrating T cells in the pathology of lupus nephritis is unclear. This study was undertaken to investigate whether CD4+ T cell responses to a surrogate mesangial antigen can initiate glomerulonephritis.

Methods: Ovalbumin (OVA) was deposited in the glomerular mesangium of C57BL/6 (B6) mice using anti-α8-integrin immunoliposomes (α8ILs). This was followed by injection of activated OVA-reactive CD4+ transgenic OT2 T cells. Trafficking of antigen-specific OT2 T cells to kidneys and lymph nodes was studied by flow cytometry. Glomerular pathology and immune cell infiltration was characterized by immunostaining. Role of CCR2 deficiency on T cell-mediated glomerulonephritis was investigated using B6.ccr2(-/-) mice.

Results: α8ILs delivered OVA specifically to the renal glomeruli. Adoptively transferred OT2 T cells preferentially accumulated in renal lymph nodes and in the renal cortex. Kidneys showed glomerular inflammation with recruitment of endogenous T cells, dendritic cells and macrophages. T cell-mediated inflammation induced mesangial cell activation and an increase in glomerular MCP1 and fibronectin. The formation of inflammatory foci was driven by Ly6C monocytes and was CCR2 dependent.

Conclusions: The findings from this study show that T cells reactive with antigens in the mesangium are sufficient to initiate glomerular pathology. Antigen-specific CD4 T cells act by inducing glomerular MCP1 production which mediates recruitment of inflammatory monocytes resulting in glomerulonephritis. Thus, down-modulation of T cell responses within the kidneys of lupus patients will be a beneficial therapeutic approach.