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Jing Hua, Takenori Inomata, William Stevenson, Tina Shiang, Yihe Chen, Jeffrey Bluestone, Reza Dana; Pathological Conversion of Regulatory T Cells Cause Disruption of Immune Privilege. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Disruption of immune privilege is associated with premature transplant rejection and autoimmunity, often leading to devastating inflammation and irreparable tissue damage. We examine the conversion of regulatory T cells (Tregs) into inflammatory cells (plasticity) in disruption of immune privilege in corneal transplantation model.
We utilized transgenic mice with a Foxp3-lineage reporter construct (Foxp3-GFPXR26-RFP) to trace the past and current expression of Foxp3 in Tregs; and measured the integrity of immune privilege by corneal graft survival rate. Adoptive transfers of isolated Treg subsets were carried out in healthy graft recipients vs. those with dry eye disease. The detailed phenotype of Foxp-3 lineage cells was analyzed using flow cytometry; their function was assessed using an ex vivo Treg suppression assay. ELISA and qPCR were used to assess cytokine expression associated with Treg plasticity.
We found that inflammation in dry eye condition leads to high conversion of Foxp3+ Tregs to inflammatory exTregs, which no longer support immune privilege, leading to swift allograft rejection (55.6% vs. 11.1% survival rate, n=9, p=0.019 Log-Rank). The Treg suppression assay showed Tregs from dry eye recipients lost significant suppressive function at day 21 (82.3% in healthy control vs. 56.8% in dry eye, n=3-6, **P<0.01). Adoptive transfer of Tregs (CD4+CD25+) from naïve BALB/c mice recipients with dry eye led to dramatic increase of corneal graft survival (0% [non-Treg] vs. 50% [Treg] n=10; χ2=11.25, p=0.0008, Log-Rank). Adoptive transfer of Treg subsets demonstrated that the peripherally induced neuropilin-1 negative Tregs (pTreg) are the key regulators of allo-tolerance, but are highly susceptible to environmental cues including interleukin-6 (IL-6) and IL-23, which promote their conversion to pathogenic exTregs. Neutralization of IL-6 and IL-23 with simultaneous transfer of isolated pTregs demonstrated significant less conversion into inflammatory exTregs, and successful rescue of corneal grafts (90% survival vs. 50% control thymic Tregs; n=10, χ2=4.503, p=0.0338, Log-Rank) in dry eye recipients (10% initial survival).
These results provide the first evidence that disruption of immune privilege is mediated by pathological conversion of Tregs. Preventing the pathological conversion of pTregs may be a novel strategy to ameliorate graft survival.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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