President’s Award 2021 recognizes research that paves the way for new cell therapies to treat autoimmune diseases and inflammation
Zhongmin Wang, a fifth-year doctoral student at Gerstner Sloan Kettering Graduate School of Biomedical Sciences (GSK), received the President’s Award 2021.
The competitive award is presented annually and was created by GSK Chairman of the Board, Louis V. Gerstner, Jr., whose school is named after. This year’s President’s Award, in the amount of $ 2,000, highlights Mr. Wang’s winning submission, which was published last month in Natural immunology.
Dr. Wang and his co-authors specially designed mouse models for the project, which demonstrated that regulatory T cells (Treg) are fully functional under conditions of established inflammation and are able to reverse, in addition to preventing, fatal autoimmunity. The results pave the way for the development of Treg cell-based therapies for a wide range of autoimmune diseases and inflammatory disorders that increase cancer risk.
“I am honored that the award committee recognized the exceptional quality and potential impact of this research,” said Wang, who is conducting his thesis studies in the lab of his thesis mentor, Alexander Rudensky, chairman of the Memorial Sloan Immunology Program. Kettering and lead author of the study.
“The award is a tremendous inspiration for me to continue my research in the area of regulatory T cell biology,” says Wang, who co-led the study with his colleague, Wei Hu, a member of Dr. Rudensky’s lab.
Below, Mr. Wang describes his award-winning research.
Regulatory T cells function in established systemic inflammation and fatal reverse autoimmunity
Regulatory T cells (Treg), characterized by the expression of the transcription factor defining the line Foxp3, are specialized CD4+ T cells with immunosuppressive function. Foxp3-deficient mice lack Treg cells and spontaneously succumb to endemic lympho- and myeloproliferative disease within four weeks of life. Likewise, the continued ablation of Treg cells in adulthood in Foxp3DTR mouse, in which Foxp3-expressing cells can be selectively killed by treatment with diphtheria toxin, also causes fatal autoimmune inflammation.
In humans, FOXP3 mutations lead to IPEX syndrome (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) due to a lack of functional Treg cells, and the insufficiency or dysfunction of Treg cells is implicated in multiple autoimmune disorders, such as type I diabetes, rheumatoid arthritis, and multiple sclerosis. Collectively, these results unequivocally demonstrated an indispensable role of Treg cells in preventing the onset of fatal autoimmunity.
However, whether Treg cells can function effectively under conditions of established systemic inflammation or reverse severe autoimmunity and prevent its relapse has been the subject of intense debate. Much 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 the treatment of autoimmune diseases. Previous studies attempting to answer this question, both in clinical and experimental settings, have mostly produced negative or inconclusive results, as the adoptive transfer models on which they have relied have inherent problems such as failure of the graft or reception of the appropriate tissue.
To meet the need for a better mouse model, we created a reversible model Foxp3 null allele (Foxp3Lox-STOP-Lox) whose expression is by default prevented by a transcriptional termination cassette but can be saved by the Cre recombinase which can be activated by tamoxifen. This allowed us to acutely and specifically activate Foxp3 expression in vivo in Treg cell line “aspirator Treg cells” that were generated under physiological conditions, thereby bypassing artifacts associated with adoptive transfers. These “budding Treg cells” were originally devoid of suppressive properties due to the lack of Foxp3 protein, but became fully functional once Foxp3 expression was restored.
By treating these mice at two weeks of life when the autoimmune disease is pronounced, we demonstrated that restoring Foxp3 expression and the resulting functional Treg cells completely reversed pathologies and tissue dysfunction, and resolved fatal autoimmune inflammation, including T cell activation and proliferation, expansion of myeloid cells, elevated levels of serum antibodies and acute phase proteins, as well as lymphocyte infiltration into tissues. Transcriptomic profiling and functional testing indicated that the recovered Treg cells were more suppressive, developed 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 stably persisted without showing signs of exhaustion and provided long-term protection against relapse of autoimmunity. Through developmental trajectory analysis based on single-cell transcriptomic data, we demonstrated that stably persistent Treg cells in resuscitated mice resemble long-lived ones identified in normal healthy mice with approaches genetic fate mapping, both showing high activation and increased suppressive function.
In addition, we have discovered a distinct subset of Treg cells with enhanced, enriched self-renewal properties in rescued mice as well as in neonatal wild-type mice. Characterized by increased expression of Epcam, Lrrc32, as well as receptors for the cytokines IFNγ, IL-4 and IL-2, these cells potentially contribute to the maintenance of the Treg cell pool.
Our study demonstrated that Treg cells are highly functional in a severely inflammatory environment and are able to reverse and restrict, in addition to preventing, complex autoimmune inflammation. These findings pave the way for the development of Treg cell-based therapies for autoimmune diseases and inflammation predisposing to cancer.