Introduction: Neuropilin-1 (NRP1) is a transmembrane glycoprotein that functions as a co-receptor for class III/IV semaphorins, VEGF, and several other growth factors. NRP1 has been previously shown to be highly expressed on CD4+Foxp3+ regulatory T cells (Treg), with a suggested role in the migration, and possibly also suppressive function, of these cells. Much of this work has been performed in cancer models, but to date, little is known of NRP1's role in transplantation.

Methods: Female B6 mice on a wild-type background (WT) or with selective cre-mediated depletion of NRP1 on CD4+ T cells (NRP1-KO) were transplanted with tail skin grafts from either Balb/c (major mismatch) or male B6 (minor mismatch) donors and graft survival was recorded. WT B6 recipients with gender-matched syngeneic graftsserved as controls and were sacrificed on POD 100. Draining lymph nodes were removed at the time of rejection and FACS stained for NRP1 and activation markers CD25 and CD69.

Results:1)In the major mismatch setting, both WT and NRP1-KO mice rejected grafts around 10 days after transplantation.In the minor mismatch setting, WT recipients rejected grafts within 10-20 days, while NRP1-KO recipients presented graft survival of up to 40 days. 2) In naïve non-grafted mice and those with syngeneic grafts, NRP1 was found on only few CD4+FoxP3- conventional T cells (Tconv) and CD8+ T cells (<5%), but on a high proportion of CD4+FoxP3+ Treg (~80%) and CD11c+ DC (50-60%). 3)In major and minor mismatch settings, WT recipients displayed no major changes for NRP1 expression within CD4+ Treg, but showed NRP1 upregulation to about 20%, 10% and 80% on CD4+Tconv, CD8+T cells and CD11c+DC, respectively. NRP1-KO recipients presented complete absence of NRP1 from CD4+ Treg and CD4+ Tconv but NRP1 upregulation on CD8+ T cells and CD11c+ DC at levels similar to WT animals.4)CD25 and CD69 were upregulated on both, WT and NRP1-KO, CD4+ Tconv and CD8+ T cells following transplantation, reflecting allogeneic activation. Overall, expression levels were slightly higher in the major as compared to the minor mismatch groups.

Conclusion: NRP1 expression has been reported earlier to be beneficial for Treg. We show that NRP1 is upregulated on T effector cells and DC upon allogeneic stimulation, and that its deletion from CD4+ T cells prolongs graft survival in a minor mismatch skin transplant model. We suggest that in this transplant setting, NRP1 expression is not crucial for Treg suppressive function but rather necessary for CD4+ T cell activation and effector function.

CITATION INFORMATION: Lee E, Kim H, Demirci G. Role of NRP1 in CD4+ T Cell Allo-Activation. Am J Transplant. 2016;16 (suppl 3).

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