It is well established that Foxp3+ regulatory T cells (Tregs) are required to maintain immune system homeostasis, and can modulate immune responses to both self- and foreign antigens. However, the factors that guide the ability of Tregs to modulate immune responses in vivo remain poorly understood. Recent studies have shown that Tregs can utilize transcription factors that are associated with conventional CD4+ T cell differentiation to acquire properties that facilitate their ability to regulate the corresponding immune response (e.g. Th1 versus Th17). While these studies have established that differentiation of Tregs into effector phenotypes can occur, little is currently known about factors that can govern their development and associated activity in different inflammatory settings. How and whether Treg differentiation could be modulated in therapeutic settings is similarly not well understood. In prior funding periods we developed lineages of transgenic mice that express the influenza virus hemagglutinin as a surrogate self-antigen, and can co-express HA-specific CD4+ T cell receptors (TCRs). In some lineages the self-HA induces the abundant formation of HA-specific Foxp3+ Tregs, but where HA expression has been targeted to MHC Class II+ antigen presenting cells (APCs) autoreactive HA-specific CD4+ T cells induce the development of autoimmune inflammatory arthritis; moreover, varying the affinity of the autoreactive TCR for the HA can lead to the involvement of different cytokine and cellular pathways in arthritis development. Preliminary studies have found that administration of HA-specific Tregs to pre-arthritic mice can prevent arthritis development if they become activated in an environment that promotes upregulation of the chemokine receptor CCR6. Conversely, Tregs that become activated in environments that promote CXCR3+ upregulation are ineffective against arthritis development, but can modulate anti-viral immune responses in the lungs.
Aim 1 will determine how differentiation in distinct inflammatory environments shapes Treg activity, and assess the extent to which the ability of Tregs to regulate qualitatively distinct immune responses at distinct sites (e.g. inflammatory arthritis versus respiratory virus infection) is dependent upon and dictated by the expression of appropriate chemokine receptors.
Aim 2 will examine how interactions with different APC subsets can direct Tregs to acquire distinct effector phenotypes, and evaluate how Tregs differentiate when interactions with APC costimulatory molecules are inhibited by antibody blockade.
Aim 3 will determine whether the ability or tendency of Tregs to acquire effector phenotypes is determined by their ability to expand in response to TCR stimulation, and examine whether modifying TCR signaling alters the ability of the Tregs to acquire distinct effector phenotypes. These studies will define factors that can determine Treg activity in vivo by directing their differentiation into distinct effector phenotypes, and will examine how the development of different types of effector Treg might be manipulated in therapeutic settings.
CD4+Foxp3+ regulatory T cells (Tregs) are required to prevent autoimmunity and maintain immune system homeostasis, as evidenced by the IPEX (Immunodysregulation, polyendocrinopathy, and enteropathy, X- linked) syndrome that develops in humans bearing mutations in the Foxp3 gene. Tregs have been found to impact immune responses in a variety of settings such as infection, transplantation, and cancer, and their failure to effectively regulate autoreactive CD4+ T cells has been implicated a wide variety of autoimmune diseases, including rheumatoid arthritis, diabetes and multiple sclerosis. The studies in this proposal will examine how Tregs recognize self-antigens in autoimmune environments, and define the role(s) that differentiation of Tregs into distinct effector phenotypes can play in directing their activity. Understanding these processes will provide insights into reasons why autoimmune diseases can develop and will aid in the application of Tregs to therapeutic settings.
