Intravascular patrolling monocytes initiate CD4+ T cell-mediated inflammation in the glomerular microvasculature.

Autoimmune glomerulonephritis is a leading cause of end-stage renal failure. Effector CD4+ T cells can rapidly induce glomerular inflammation in an antigen-dependent manner. However it is unclear how these cells recognise antigens within the glomerular microvasculature. The aim of this study was to investigate the mechanisms by which effector CD4+ T cells initiate glomerular inflammation. Intravital multiphoton microscopy of kidneys of MHCII-eGFP mice revealed that in the absence of inflammation, intraglomerular expression of MHCII was restricted to circulating leukocytes. Following transfer of activated OT-II (CD4+) T cells, both intravascular MHCII+ leukocytes and effector CD4+ T cells underwent periods of retention and migration in the glomerular capillaries and regularly interacted with each other. To induce antigen-dependent glomerular inflammation, the OT-II peptide pOVA323-339 was deposited in glomeruli via conjugation to 8D1, a mAb specific for the glomerular basement membrane. Mice administered the 8D1/pOVA conjugate displayed increased retention of activated CD4+ T cells within 2 hours, indicating local antigen recognition. Of the circulating MHCII-expressing leukocytes, both B cells and monocytes underwent retention in the glomerular capillaries, although MHCII+ monocytes were retained in the glomerulus for significantly longer periods. Furthermore, while the absence of B cells did not affect CD4+ T cell-dependent inflammation, monocyte depletion significantly reduced this response. These data indicate that intravascular MHCII+ patrolling monocytes initiate CD4+ T cell responses in the glomerular microcirculation and this can result in glomerular inflammation.