Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes

Abstract

Although effector CD4+ T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown. Here we show the process of intravascular antigen recognition using intravital multiphoton microscopy of glomeruli. CD4+ T cells undergo intravascular migration within uninflamed glomeruli. Similarly, while MHCII is not expressed by intrinsic glomerular cells, intravascular MHCII-expressing immune cells patrol glomerular capillaries, interacting with CD4+ T cells. Following intravascular deposition of antigen in glomeruli, effector CD4+ T-cell responses, including NFAT1 nuclear translocation and decreased migration, are consistent with antigen recognition. Of the MHCII+ immune cells adherent in glomerular capillaries, only monocytes are retained for prolonged durations. These cells can also induce T-cell proliferation in vitro. Moreover, monocyte depletion reduces CD4+ T-cell-dependent glomerular inflammation. These findings indicate that MHCII+ monocytes patrolling the glomerular microvasculature can present intravascular antigen to CD4+ T cells within glomerular capillaries, leading to antigen-dependent inflammation.

Monocyte heterogeneity and functions in cancer

“…While presentation of tumor Ags is generally thought to occur within primary tumor sites or their draining lymph nodes, a recent report demonstrated that intravascular MHCII + monocytes are able to present Ag to CD4 + T cells within inflamed glomeruli vasculature . Whether similar interactions between T cells and monocytes can occur within tumor vasculature or following engulfment of tumor‐derived material in circulation remains an interesting direction for further exploration.…”

“…82 While presentation of tumor Ags is generally thought to occur within primary tumor sites or their draining lymph nodes, a recent report demonstrated that intravascular MHCII + monocytes are able to present Ag to CD4 + T cells within inflamed glomeruli vasculature. 84…”

Animal Models of ANCA Associated Vasculitis

“…NETs are released within the microvasulature, where they not only contribute to endothelial injury but also may activate TLRs expressed on resident tissue cells (48,56) and may promote local alternate complement pathway activation (57). They also deposit the autoantigens MPO and PR3 in target tissues, making them potentially able to be presented to effector antigen-specific T cells (58). While mechanistic understanding of NETs has largely been gleaned from in vitro studies (54,59), the functional role of NETs as effectors of injury has also been translated to animal models of AAV.…”

“…Glomerular injury is mild to minimal after transfer of cells specific to an irrelevant specificity (ovalbumin) (18,20). Antigen can be presented intravascularly by patrolling monocytes (58) and may also be presented locally by glomerular endothelial cells, while later in disease dendritic cells infiltrate diseased glomeruli in human AAV (82).…”

Unraveling the host's immune response to infection: Seeing is believing

“…103 On the other hand, uptake of bacteria by resident macrophages may actually impede the development of an adaptive immune response during UTI, as the depletion of these cells was shown to enhance bacterial uptake by dendritic cells and reduce bacterial burden upon secondary challenge. 104 IVM has been utilized to investigate immunologic responses in the urinary tract [105][106][107][108][109][110][111][112] ; however, studies focused on infection are more limited. [113][114][115][116] IVM has helped elucidate the mechanisms that underlie leukocyte recruitment dynamics to the bladder 113 and pathophysiology in the kidneys [114][115][116] during infection with Escherichia coli.…”