Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer

We examined the phenotype and function of CD4(+) T cells expressing the semaphorin III receptor neuropilin-1 (Nrp1) in human lymph nodes and peripheral blood. In lymph nodes, Nrp1 identified a small regulatory CD4(+) CD25(high) T-cell subpopulation (Nrp1(+) Treg) that expressed higher levels of Forkhead box P3 (Foxp3) message and protein than Nrp1(-) Treg, and various molecular markers of activated Treg, i.e. CD45RO, human leucocyte antigen (HLA)-DR and glucocorticoid-induced tumour necrosis factor receptor (GITR). Similarly to conventional Treg, Nrp1(+) Treg proliferated poorly in vitro, and exerted contact-dependent in vitro suppression of T-cell proliferation and cytokine secretion. However, Nrp1(+) Treg were more efficient than Nrp1(-) Treg at inducing suppression. Nrp1 was also expressed on a small subpopulation of CD25(int) and CD25(-) CD4(+) T cells that expressed more Foxp3, CD45RO, HLA-DR and GITR than their Nrp1(-) counterparts. In contrast, in peripheral blood Nrp1 identified a minor CD4(+) T-cell subset that did not display the phenotypic features of Treg lacking Foxp3 expression and marginally expressing CD25. Hence, the function of Nrp1(+) CD4(+) T cells seemingly depends on their anatomical location. In a previous report, we proposed that Treg may curb the anti-tumour T-cell response in cervical cancer. We show here that Treg and Nrp1(+) Treg levels dropped in the tumour-draining lymph nodes of patients with cervical cancer following preoperative chemoradiotherapy in a direct relationship with the reduction of tumour mass, suggesting that suppressor cell elimination facilitated the generation of T cells mediating the destruction of the neoplastic cells left behind after cytotoxic therapy.