Abstract
CD4+CD25+Foxp3+ Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3+ Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17+ or IFNγ+ ‘exFoxp3’ T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1− peripherally-derived Tregs are particularly susceptible to conversion to IL-17+/IFNγ+ exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.
Highlights
CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in mediating immunological self-tolerance
In this study, using a double transgenic mouse model that permits Foxp[3] lineage tracing, we investigated the phenotypic plasticity of Foxp3+ Tregs in a well-characterized murine model of corneal transplantation[12,13,14]
Our results demonstrated that induction of dry eye disease (DED) in graft recipients before performing corneal transplantation resulted in significantly higher graft opacity scores compared to healthy hosts (Fig. 1A)
Summary
CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in mediating immunological self-tolerance. Thymus-derived tTregs, and their peripherally induced counterparts pTregs, provide essential suppressive mechanisms against deleterious immune-mediated inflammation. These specialized T cell subsets are clonal groupings within a much larger, heterogeneous population of CD4+ T cells – including Th1, Th2 and Th17 cells. The reprogramming of Tregs towards a memory T cell phenotype has been shown to promote inflammation in autoimmune disease[6]. We demonstrate that inflammation in the ocular tissue leads to the loss of Foxp[3] in Tregs, and their conversion to ‘exFoxp[3] cells’, which express the pro-inflammatory cytokines IL-17 and/or IFN-γ. Conversion to exFoxp[3] cells These results provide evidence that pathological conversion of Tregs contributes to the loss of corneal immune privilege and allograft rejection
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call