Intragraft memory-like CD127hiCD4+Foxp3+ Tregs maintain transplant tolerance
Yuanfei Zhao, Leigh Nicholson, Hannah Wang, Yi Wen Qian, Wayne J. Hawthorne, Elvira Jimenez-Vera, Brian S. Gloss, Joey Lai, Adwin Thomas, Yi Vee Chew, Heather Burns, Geoff Y. Zhang, Yuan Min Wang, Natasha M. Rogers, Guoping Zheng, Shounan Yi, Stephen I. Alexander, Philip J. O’Connell, Min Hu
Yuanfei Zhao, Leigh Nicholson, Hannah Wang, Yi Wen Qian, Wayne J. Hawthorne, Elvira Jimenez-Vera, Brian S. Gloss, Joey Lai, Adwin Thomas, Yi Vee Chew, Heather Burns, Geoff Y. Zhang, Yuan Min Wang, Natasha M. Rogers, Guoping Zheng, Shounan Yi, Stephen I. Alexander, Philip J. O’Connell, Min Hu
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Research Article Transplantation

Intragraft memory-like CD127hiCD4+Foxp3+ Tregs maintain transplant tolerance

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in suppressing transplant rejection, but their role within the graft and heterogeneity in tolerance are poorly understood. Here, we compared phenotypic and transcriptomic characteristics of Treg populations within lymphoid organs and grafts in an islet xenotransplant model of tolerance. We showed Tregs were essential for tolerance induction and maintenance. Tregs demonstrated heterogeneity within the graft and lymphoid organs of tolerant mice. A subpopulation of CD127hi Tregs with memory features were found in lymphoid organs, presented in high proportions within long-surviving islet grafts, and had a transcriptomic and phenotypic profile similar to tissue Tregs. Importantly, these memory-like CD127hi Tregs were better able to prevent rejection by effector T cells, after adoptive transfer into secondary Rag–/– hosts, than naive Tregs or unselected Tregs from tolerant mice. Administration of IL-7 to the CD127hi Treg subset was associated with a strong activation of phosphorylation of STAT5. We proposed that memory-like CD127hi Tregs developed within the draining lymph node and underwent further genetic reprogramming within the graft toward a phenotype that had shared characteristics with other tissue or tumor Tregs. These findings suggested that engineering Tregs with these characteristics either in vivo or for adoptive transfer could enhance transplant tolerance.

Authors

Yuanfei Zhao, Leigh Nicholson, Hannah Wang, Yi Wen Qian, Wayne J. Hawthorne, Elvira Jimenez-Vera, Brian S. Gloss, Joey Lai, Adwin Thomas, Yi Vee Chew, Heather Burns, Geoff Y. Zhang, Yuan Min Wang, Natasha M. Rogers, Guoping Zheng, Shounan Yi, Stephen I. Alexander, Philip J. O’Connell, Min Hu

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Figure 8

IL-7 stimulation induces enhanced phosphorylation of STAT5 in CD127hi Tregs.

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IL-7 stimulation induces enhanced phosphorylation of STAT5 in CD127hi Tr...
(A) Baseline mean fluorescence intensity (MFI) of STAT5 phosphorylation (p-STAT5) on Tregs (gated on CD4+GFP+) and Foxp3– CD4+ (gated on CD4+GFP– cells) of the spleen and/or DLN from mouse recipients receiving CTLA4-Fc/MR1 treatment at day 100 (n = 5) and naive mice (n = 5) under PBS is shown. (B) Representative histograms of pSTAT5 expression on splenic CD4+GFP– cells (blue shade — naive group, blue line — tolerant group) and CD4+GFP+ Tregs (red line — naive group, red shade — tolerant group), induced by IL-2 or IL-7 stimulation, and PBS (black line). (C) MFI of p-STAT5 expression on Tregs (n = 5) and CD4+GFP– cells (n = 5) from the spleen, DLN, and/or graft of tolerant mice (n = 5) and naive mice (n = 5) induced by IL-2 or IL-7 stimulation compared with the baseline under PBS (n = 10, including Tregs and CD4+GFP– cells in naive mice; and n = 18, including Treg and CD4+GFP– cells in tolerant mice). (D) IL-7–induced p-STAT5 on Tregs (red) and CD127hi Tregs (yellow) of spleens, DLNs, and grafts in tolerant mice is shown. A 1-way ANOVA was used in A and C, and the paired 2-tailed t test was used in D. Data were from 5 independent experiments and shown as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001.