2021 Chairman’s Prize Honors Research That Paves Way for New Cell-Based Therapies to Treat Autoimmune Diseases and Inflammation

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Zhongmin Wang

Zhongmin Wang

Zhongmin Wang, a fifth-year doctoral student in the Gerstner Sloan Kettering Graduate School of Biomedical Sciences (GSK), has been awarded the 2021 Chairman’s Prize.

The competitive award is presented annually and was established by GSK’s Board of Trustees Chair Louis V. Gerstner, Jr. for whom the school is named. This year’s Chairman’s Prize, in the amount of $2,000, shines a light on Mr. Wang’s winning submission, which was published last month in Nature Immunology

Mr. Wang and his coauthors specifically designed mouse models for the project, which demonstrated that regulatory T (Treg) cells are fully functional under conditions of established inflammation and are capable of reversing, in addition to preventing, fatal autoimmunity. The results pave the way for the development of Treg cell-based therapies for a broad spectrum of autoimmune diseases and inflammatory disorders that raise the risk of cancer.

Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity

Read the Nature Immunology paper »

“I am honored that the prize committee recognized the outstanding quality and potential impact of this research,” says Mr. Wang, who is conducting his dissertation studies in the laboratory of his thesis mentor, Alexander Rudensky, Chair of the Immunology Program at Memorial Sloan Kettering and senior author of the study.

“The award is a tremendous inspiration for me to pursue further research in the field of regulatory T cell biology,” continues Mr. Wang, who co-led the study with his colleague, Wei Hu, a Fellow in Dr. Rudensky’s lab.

Below, Mr. Wang describes his prize-winning research.

Regulatory T cells Function in Established Systemic Inflammation and Reverse Fatal Autoimmunity

Regulatory T (Treg) cells, characterized by the expression of the lineage-defining transcription factor Foxp3, are specialized CD4+ T cells with immunosuppressive function. Foxp3-deficient mice lack Treg cells and spontaneously succumb to rampant lympho- and myeloproliferative disease within four weeks of life. Similarly, continuous ablation of Treg cells during adulthood in Foxp3DTR mice, in which Foxp3-expressing cells can be selectively killed by diphtheria toxin treatment, causes lethal autoimmune inflammation as well.

In humans, FOXP3 mutations result in the autoimmune disease IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome due to a lack of functional Treg cells, and Treg cell insufficiency or dysfunction is implicated in multiple autoimmune disorders, such as type I diabetes, rheumatoid arthritis, and multiple sclerosis. Collectively, these findings have unequivocally demonstrated an indispensable role of Treg cells in preventing the onset of fatal autoimmunity.

However, whether Treg cells can effectively function under conditions of established systemic inflammation or reverse severe autoimmunity and prevent its relapse has been a subject of intense debate. A large body of work has shown that inflammatory mediators can either inhibit the suppressive function of Treg cells or render pro-inflammatory effector cells refractory to suppression. This raises questions about the potential for therapeutic use of Treg cells in treating autoimmune diseases. Previous studies attempting to address this question, in both clinical and experimental settings, mostly generated negative or inconclusive results, because the adoptive transfer models they relied on have intrinsic issues such as failure to engraft or home to the appropriate tissue.

To address the need for a better mouse model, we created a reversible Foxp3 null allele (Foxp3Lox-STOP-Lox) whose expression is by default prevented by a transcriptional termination cassette but can be rescued by tamoxifen-activatable Cre recombinase. This allowed us to acutely and specifically activate Foxp3 expression in vivo in the Treg cell lineage-committed “Treg wannabe cells” that were generated under physiological conditions, hence bypassing the artifacts associated with adoptive transfers. Such “Treg wannabe cells” were originally devoid of suppressive properties due to lack of Foxp3 protein but became fully functional once Foxp3 expression was restored.

By treating these mice at two weeks of life when autoimmune disease is pronounced, we have demonstrated that restoration of Foxp3 expression and the resulting functional Treg cells completely reversed tissue pathologies and dysfunction, and resolved the lethal autoimmune inflammation, including T cell activation and proliferation, myeloid cell expansion, elevated serum antibody and acute phase protein levels, as well as lymphocytic infiltration in tissues. Transcriptomic profiling and functional assays indicated that the rescued Treg cells were more suppressive, elaborated higher levels of effector molecules, and participated in tissue repair.

Surprisingly, Treg cells generated as a cohort in response to a single dose of tamoxifen treatment persisted stably without exhibiting signs of exhaustion and provided long-term protection against relapse of autoimmunity. Through developmental trajectory analysis based on single-cell transcriptomic data, we have demonstrated that the stably persisting Treg cells in resurrected mice resemble the long-lived ones identified in healthy normal mice with genetic fate-mapping approaches, both showing elevated activation and increased suppressive function.

Moreover, we discovered a distinct subset of Treg cells with enhanced self-renewing properties enriched in rescued mice as well as neonatal wild-type mice. Characterized by heightened expression of Epcam, Lrrc32, as well as receptors for the cytokines IFNγ, IL-4, and IL-2, these cells are potentially contributing to the maintenance of the Treg cell pool.

Our study demonstrated that Treg cells are highly functional under a severely inflammatory environment and are capable of reversing and restraining, in addition to preventing, complex autoimmune inflammation. These results pave the way for the development of Treg cell-based therapies for autoimmune diseases and cancer-predisposing inflammation.