Self-Specific Memory Regulatory T Cells Protect Embryos at Implantation in Mice

Abstract

Regulatory T cells (Tregs) play crucial roles in both fetal and tumor development. We recently showed that immunosurveillance by pre-existing CD44hiCD62Llow activated/memory Tregs (amTregs) specific for self-antigens protects emergent tumor cells in mice. This Treg response of a memory type is more rapid than and dominates the anti-tumor response of tumor-specific effector T cells. Here, we report striking similarities between the early Treg responses to embryo and tumor implantation. Tregs are (i) rapidly recruited to uterus-draining lymph nodes and activated in the first days after embryo implantation in both syngeneic and allogeneic matings; (ii) they express the markers of the amTreg subset; and (iii) are at least in part self-antigen-specific, as seen in tumor emergence. Unlike in the tumor emergence setting, however, for which pre-immunization against tumor antigens is sufficient for complete tumor eradication even in the presence of Tregs, Treg depletion is additionally required for high frequencies of fetus loss after pre-immunization against paternal tissue antigens. Thus, amTregs play a major role in protecting embryos in both naïve and pre-immune settings. This role and the ensuing therapeutic potential are further highlighted by showing that Treg stimulation, directly by low-dose interleukin-2 or indirectly by Fms-related tyrosine-kinase-3 ligand, lead to normal pregnancy rates in a spontaneous abortion-prone model.

Regulatory T Cells Orchestrate Similar Immune Evasion of Fetuses and Tumors in Mice

“…2B-D). Altogether, these results are in line with the early recruitment and activation of Tregs in the pregnant uterus (25), and they indicate that Foxp3 does act as a transcriptional activator and repressor in vivo.…”

“…Reductionist approaches have highlighted the role of Tregs in maternal-fetal tolerance (25). Therefore, we asked what the behavior of Treg signatures could be within our dataset.…”

“…We previously showed that embryo or tumor cell implantation leads to a similar brisk recruitment of self-specific activated/memory Tregs (21,25). To analyze the similarities between tolerance to The Journal of ImmunologyFIGURE 2.…”

“…Tregs specific for selfantigens are recruited in tumor or uterine draining lymph nodes before Teffs are recruited, with the functional relevance of this being supported by the fact that Treg depletion leads to fetal (22,23) or tumor (24) immune rejection. These observations led us to hypothesize that tumors hijack mechanisms of tolerance initially selected during evolution of the mammalian immune system to protect fetuses (25).…”

TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice

“…Indeed, we reported the existence of two Treg-cell subsets in nonmanipulated mice: CD44 low CD62L high resting/naïve Treg cells (nTreg cells), quiescent and long-lived, and CD44 high CD62L low activated/memory Treg cells (amTreg cells), extensively dividing and expressing multiple activation markers [24]. Our results suggest that amTreg cells recognize self-antigens and control autoimmune disease development as well as antitumor and antifetus effector immune responses [24][25][26]. We thus hypothesized that the repertoire of amTreg cells should be less diverse than nTreg cells and enriched for self-antigen-specific TCRs.…”