Key Points
Western diet feeding increases Nrp1 on Foxp3− CD4 T cells in ApoE−/− mice.
Nrp1+Foxp3− CD4 T cells are highly proliferative and atherogenic.
Nrp1+Foxp3− CD4 T cells preferentially migrate to the aorta and PaLN.
Abstract
Neuropilin 1 (Nrp1) is a type I transmembrane protein that plays important roles in axonal guidance, neuronal development, and angiogenesis. Nrp1 also helps migrate thymus-derived regulatory T cells to vascular endothelial growth factor (VEGF)-producing tumors. However, little is known about the role of Nrp1 on CD4 T cells in atherosclerosis. In ApoE−/− mice fed a Western diet for 15 wk, we found a 2-fold increase in Nrp1+Foxp3− CD4 T cells in their spleens, periaortic lymph nodes, and aortas, compared with chow-fed mice. Nrp1+Foxp3− CD4 T cells had higher proliferation potential, expressed higher levels of the memory marker CD44, and produced more IFN-γ when compared with Nrp1− CD4 T cells. Treatment of CD4 T cells with oxLDL increased Nrp1 expression. Furthermore, atherosclerosis-susceptible mice selectively deficient for Nrp1 expression on T cells developed less atherosclerosis than their Nrp1-sufficient counterparts. Mechanistically, we found that CD4 T cells that express Nrp1 have an increased capacity to migrate to the aorta and periaortic lymph nodes compared to Nrp1− T cells, suggesting that the expression of Nrp1 facilitates the recruitment of CD4 T cells into the aorta where they can be pathogenic. Thus, we have identified a novel role of Nrp1 on CD4 T cells in atherosclerosis. These results suggest that manipulation of Nrp1 expression on T cells can affect the outcome of atherosclerosis and lower disease incidence.
Footnotes
This work was supported by the American Heart Association (13POST16990031 to D.E.G. and 19POST34450020 to L.E.P.), the American Diabetes Association (7-12-MN-13 to D.E.G. and C.C.H.), and the National Institutes of Health (P01 HL055798 and P01 HL136275 to C.C.H., R01 HL112276 to C.C.H., T32 AI125279-01 Training in Immunological Mechanisms Training Grant to L.E.P., and S10 RR027366-01A1 to the La Jolla Institute for Immunology Flow Cytometry Core Facility).
The online version of this article contains supplemental material.
- Received February 27, 2019.
- Accepted October 21, 2019.
- Copyright © 2019 by The American Association of Immunologists, Inc.
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