Both Regulatory T Cells and Antitumor Effector T Cells Are Primed in the Same Draining Lymph Nodes during Tumor Progression

Abstract

The peripheral tolerance mechanism prevents effective antitumor immunity, even though tumor cells possess recognizable tumor-associated Ags. Recently, it has been elucidated that regulatory T cells (Treg) play a critical role in maintaining not only self-tolerance, but also tolerance of tumor cells. However, because the Treg that maintain self-tolerance arise naturally in the thymus and are thought to be anergic in peripheral, it is still unclear where and when Treg for tumor cells are generated. In this study we analyze tumor-draining lymph nodes (LNs) and demonstrate that both antitumor effector T cells and Treg capable of abrogating the antitumor reactivity of the effector T cells are primed in the same LNs during tumor progression. The regulatory activity generated in tumor-draining LNs exclusively belonged to the CD4+ T cell subpopulation that expresses both CD25 and a high level of CD62L. Forkhead/winged helix transcription factor gene expression was detected only in the CD62LhighCD4+CD25+ T cells. CD62LhighCD4+CD25+ Treg and CD62LlowCD4+CD25+ T cells, which possess effector T cell functions, had comparable expression of LFA-1, VLA-4, CTLA-4, lymphocyte activation gene-3, and glucocorticoid-induced TNFR. Thus, only CD62L expression could distinguish regulatory CD4+CD25+ cells from effector CD4+CD25+ cells in draining LNs as a surface marker. The Treg generated in tumor-draining LNs possess the same functional properties as the Treg that arise naturally in the thymus but recognize tumor-associated Ag. CD62LhighCD4+CD25+ Treg contained a subpopulation that expressed CD86. Blocking experiments revealed that ligation of CTLA-4 on effector T cells by CD86 on Treg plays a pivotal role in regulating CD4+ effector T cells.

CD4+CD25hi regulatory T‐cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

“…29,44 Furthermore, murine studies have demonstrated that Treg responses develop parallel to Th responses as a feedback mechanism to control the size of the immune response, 45 which takes place in the same draining lymph node. 46 Isolated Tregs from chronic HCV patients inhibited HCV specific CD8 1 T-cell responses but also peptide-specific CD8 1 CTL responses against other viruses. 40, 42 Here, we found no correlation between Treg frequencies and CTL, by comparing Treg frequencies between patients who had detectable HPV16 E6E7 specific CTL in the peripheral blood and patients who were negative for HPV16 E6E7 specific CTL.…”

Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells

“…Hiura et al recently reported that both Treg and antitumor effector T cells were primed in the same TDLN of a tumor growing subcutaneously. (12). PC61 mAb are usually injected a few days before or at the time of tumor cell implantation.…”

“…Conversion of CD4 + CD25 À T cells into Treg seems rather common in tumordraining lymph nodes (TDLN; refs. [12][13][14].…”

2-Gy whole-body irradiation significantly alters the balance of CD4+CD25−T effector cells and CD4+CD25+Foxp3+T regulatory cells in mice

“…[1][2][3][4] It has been demonstrated that CD4 1 CD25 1 Treg cells are potent suppressors or regulators in controlling allergic responses, allograft rejection, antitumor immunity and microbial immunity, in addition to keeping self-tolerance. [5][6][7] It is now clear that forkhead family Foxp3 is a specific transcription factor of CD4 1 CD25 1 Treg cells, at least in mice. [8][9][10] Mutations in Foxp3 cause a similar X-linked recessive autoimmune and inflammatory disorder in humans and mice.…”