Neuropilin-1⁺regulatory T cells promote skin allograft survival and modulate effector CD4⁺T cells phenotypic signature

During allograft rejection, several immune cell types, including dendritic cells, CD4+and CD8+T cells among others, recirculate between the graft and the nearest draining lymph node, resulting in immunity against the 'foreign' tissue. Regulatory CD4+T cells are critical for controlling the magnitude of the immune response and may act to promote or maintain tolerance. They are characterized by the expression of CD25 and Foxp3, and more recently, Neuropilin-1 (Nrp1). The role of these suppressor cells during allograft rejection is not well understood. Our work shows that during graft rejection, there is an increase in the frequency of total CD4+T cells expressing Nrp1, but the expression of this molecule is downregulated in the regulatory CD4+T-cell compartment. Interestingly, the expression of the transcription factor Eos, which renders cell function stability, is also reduced. In adoptive transfer experiments, we observed that during allograft rejection: (i) natural regulatory CD4+T cells maintain high levels of Nrp1 expression, (ii) effector CD4+T cells (Nrp1-) become Nrp1+Eos+and (iii) the transfer of regulatory CD4+T cells (Nrp1+) can promote allograft survival, and also enhance the gain of Nrp1 and Eos on T-effector cells. Together, these data suggest that rejection occurs, at least in part, through the loss of Nrp1 expression on regulatory CD4+T cells, their stability or both. Additionally, the transfer of regulatory CD4+T cells (based on Nrp1 expression) permits the acceptance of the allograft, placing Nrp1 as a new target for immune therapy.