Impaired Function of Peripherally Induced Regulatory T Cells in Hosts at High Risk of Graft Rejection.

Takenori Inomata,Antonio Di Zazzo,Jing Hua,Reza Dana

doi:10.1038/srep39924

Takenori Inomata, Antonio Di Zazzo + Show 2 more

Open Access

https://doi.org/10.1038/srep39924

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Abstract

Regulatory T cells (Tregs) are crucial for allograft survival. Tregs can be divided into thymus-derived natural Tregs (tTregs) and peripherally-derived induced Tregs (pTregs). Here, we determine whether the suppressive function of Treg subsets is hampered in hosts who are at high risk for rejecting their graft. To induce graft beds that promote high risk of transplant rejection, intrastromal corneal sutures were placed two weeks prior to the transplant procedure in mice. We demonstrate that in high-risk recipients the frequencies and function of pTregs (but not tTregs) are suppressed. Reduced function of pTregs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-β. Adoptive transfer of pTregs from mice at low risk of subsequent graft rejection is able to rescue graft survival in recipients that are at high risk of rejecting their grafts. Our data suggest that impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection.

Highlights

Regulatory T cells (Tregs) maintain immune homeostasis by dampening inflammatory responses toward selfand alloantigens[1,2,3], and play a crucial role in allograft survival
Tregs isolated from draining lymph nodes (dLNs) of high-risk recipients and cultured with Tconv cells displayed ~20% less suppressive function compared to Tregs isolated from low-risk control recipients (Fig. 1E)
It is recognized that Foxp3+ Tregs are comprised of multiple subsets, and it has been suggested that peripherally-derived induced Tregs (pTregs) control antigen-specific immune responses in the periphery, whereas thymus-derived natural Tregs (tTregs) maintain general immune homeostasis[8,9,10]

Summary

Introduction

Regulatory T cells (Tregs) maintain immune homeostasis by dampening inflammatory responses toward selfand alloantigens[1,2,3], and play a crucial role in allograft survival. Studies have suggested that Foxp3+ natural Tregs (nTregs; thymic-derived Tregs [tTregs]) and peripherally-induced Tregs (pTregs) can act in concert to promote tolerance[8,9,10], but alloantigen-specific pTregs are thought to be the principal mediators of allograft tolerance[11,12,13] While these and other studies have shed light on the antigen-specificity of Tregs on graft survival, much of the results are limited to Tregs that are artificially induced in vitro through controlled alloantigen exposure, or using transgenic strains with altered immune systems[8,9,10,14,15]. We used a model of corneal transplantation[23,24] to delineate the differential function and susceptibility of tTregs and pTregs from allograft recipients – low-risk hosts with normal immune homeostatic mechanisms who develop allotolerance naturally, and high-risk hosts with inflamed graft beds who are prone to swift rejection of their transplants

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