Neuropilin-1 as mediator for Vascular Endothelial Growth Factor (VEGF)-dependent T cell migration
Final Report Abstract
The majority of Foxp3+ regulatory T cells (Tregs) expresses the VEGF co-receptor Neuropilin-1 (Nrp-1) on their surface, which contributes to Treg tumor infiltration in a VEGF- dependent manner resulting in impaired anti-tumor immune responses. Based on these findings, we aimed to analyze whether over-expression of Nrp-1 in T effector cells might be a suitable tool to induce migration into the tumor tissue resulting in reduced tumor growth. Moreover, we wondered whether Nrp-1 mediated effects on T cells are tumor-specific or have also an impact on the onset of autoimmunity. Results from the present project revealed that transfer of Nrp-1 overexpressing CD4+ and also CD8+ T cells to tumor-bearing mice do not interfere with tumor progression, but unexpectedly tend to further increase tumor growth. This effect was accompanied by reduced activation of tumor-infiltrating T cells from mice that were treated with Nrp-1 overexpressing cells. Therefore, we decided to investigate naturally occurring Nrp-1+ effector T cells, intratumoral T cells as well as the impact of hypoxia on the T cell phenotype in more detail. Stimulation of T cells under hypoxic conditions interfered with the proliferation of CD4+CD25- T cells and resulted in enhanced inhibitory activity of Tregs. These results indicate that hypoxia contributes to the immunosuppression observed during tumorigenesis. Within the tumor tissue of mice transplanted with melanoma cells, we detected significantly higher frequencies of Nrp-1 expressing CD8+ and CD4+Foxp3- T cells than in lymphoid organs. CD4+Foxp3-Nrp- 1+ T cells from naïve WT mice showed impaired proliferative activity accompanied by elevated PD-1 expression suggesting that Nrp-1 might act as an inhibitory receptor on activated effector T cells. To investigate whether T cell-expressed Nrp-1 plays a crucial role only during tumorigenesis or has also an impact on autoimmunity, we made use of the INS/HA autoimmune diabetes model. T cell-specific ablation of Nrp-1 expression accelerated the development of spontaneous autoimmune diabetes in INSHA/TCRHA transgenic mice. Strikingly, adoptive transfer experiments revealed that Nrp-1-deficient Tregs were not able to control the development of diabetes upon co-transfer with HA-specific CD4+ T cells to INS-HA/Rag2KO mice. These results clearly demonstrate that Nrp-1 expression has a strong impact on the functional properties of Foxp3+ Tregs and also on Foxp3- T effector cells. Nrp-1 deficiency in Foxp3+ Tregs resulted in an elevated inflammatory immune response not only during tumorigenesis as already described, but also accelerated the development of autoimmunity. On CD4+ effector T cells, Nrp-1 expression interfered with their proliferative activity and was associated with PD-1 expression. Thus, data from the present proposal indicate that T cell-specific blockade of Nrp-1 might be a useful therapeutic option not only to dampen the Treg function in vivo, but also to increase effector T cell activity.
Publications
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(2015). Relevance of Foxp3+ regulatory T cells for early and late phases of murine sepsis. Immunology 146: 144-56
Tatura R, Zeschnigk M, Hansen W, Steinmann J, Goncalves Vidigal P, Hutzler M, Pastille E, Westendorf AM, Buer J and Kehrmann J
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(2017). Hypoxia enhances immunosuppression by inhibiting CD4+ effector function and promoting Treg activity. Cell Physiol Biochem 41: 1271-84
Westendorf AM, Skibbe K, Adamczyk A, Buer J, Geffers R, Hansen W, Pastille E and Jendrossek V
