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The role of human forkhead box P3 in CD4⁺ T cell subsets McMurchy, Alicia Nicole

Abstract

The immune system eliminates threats to the body, but it must also prevent immune-mediated damage caused by inflammation and autoimmune disease. One way that immune responses are limited is by specialized T cells known as T regulatory (Treg) cells. The transcription factor forkhead box P3 (FOXP3) is highly expressed in Treg cells and is critical for their suppressive function. The importance of FOXP3 is demonstrated in humans with a severe autoimmune disease called immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) caused by mutations in FOXP3. Furthermore, conventional T (Tconv) cells can be re-programmed into suppressive cells upon stable over-expression of FOXP3. Therefore, there is tremendous interest in manipulating FOXP3 function and/or using Treg cells as a cellular therapy to modify immune responses of cancer patients, patients suffering from autoimmune disease, and transplantation patients. To better understand the function of FOXP3, the first goal was to investigate how mutant forms of FOXP3 found in IPEX patients were defective at programming Treg characteristics. Surprisingly, mutant forms of FOXP3 were not completely deficient at converting Tconv cells into Treg cells, suggesting that factors besides a defect in Treg cells may contribute to IPEX pathogenesis. FOXP3 is transiently up-regulated in human Tconv cells upon activation, but its role in these cells is unknown. Hence, the second goal was to examine the function of FOXP3 in Tconv cells by comparing FOXP3-deficient with wild type Tconv cells. FOXP3-deficient Tconv cells proliferated more and produced more cytokines than wild type Tconv cells. This finding suggests that FOXP3 has a role in the regulation of Tconv cell activation, especially in Th17 cells which were found to highly express activation-induced FOXP3. Lastly, the possibility of using FOXP3⁺ cells as a cellular therapy was investigated. A method to expand large, pure populations of human and cynomolgus Treg cells was developed, and ex vivo expanded Treg cells were able to promote mixed chimerism and tolerance to a kidney transplant in cynomolgus macaques. Together, this work sheds light on the role of FOXP3 in CD4⁺ T cell subsets and helps pave the way for use of Treg cell therapy in the clinic.

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