FoxP3: A Key Player in T Regulatory Biology

Abstract

The immune system has adapted mechanisms to recognize and eliminate threats, as well as to defend against self-destruction. Tolerance to self-antigens and defence against non self pathogens are maintained by the different immune cells. If there is an imbalance in T reg cells population, may leads to auto immunity. The generation of natural Treg (nTreg)/induced Treg (iTreg) and its maintenance of suppressive function are crucial for immune homeostasis. There are various surface markers on T cells like CD25, CTLA-4, OX-40 etc. and intracellular marker like FoxP3 involved in the generation and maintenance of suppressive function of Treg cells. Recent work has shown that forkhead DNA-binding proteins FoxP3, is X-chromosome-encoded transcription factor uniquely involved in the development and function of the T-regulatory cells. Lack of FoxP3 leads to development of fatal autoimmune lymphoproliferative disease in humans known as IPEX; (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) furthermore, ectopic FoxP3 expression induces conversion of effector T cells to regulatory T cells. The regulation of FoxP3 expression, and its role in maintenance of CD4+CD25+/CD25− Treg fitness still a matter of debate. Being a transcription factor FoxP3 activates/represses various effectors of the T cell activation/inhibition signal pathways. FoxP3 is an acetylated, oligomeric component of large molecular complex, actively represses transcription by recruiting enzymatic corepressors, including histone modifiers during its function. Chromatin remodeling through FoxP3 associated complexes may dynamically affect the multiple immunological signaling networks, eventually in summation lead to immune suppression. FoxP3 interacting proteins (CTLA-4, IL-2, IL-2RA, NFATC2 etc.) complex plays a central role in inducing gene transcription during the immune response. Transcription factors function as a carrier to take histone modifiers at particular locus at which they impose their effect. FoxP3 interacting with histone acetyl transferases, helps to maintain the acetylated state of FoxP3. Dynamic regulation of HAT and HDAC in FoxP3 acetylation confers the suppressive index of nTreg and iTreg cells.