Peripheral mechanisms of tolerance and immunoregulation are essential to prevent the damage potentially caused by autoreactive T cells that escape thymic tolerance induction. Among these, Treg cells expressing the FoxP3 transcription factor are the best characterized, with their ability to suppress immune and autoimmune responses, and their exciting potential for human therapy. They represent a constant proportion of CD4+ cells in lymphoid organs of a given individual, but vary markedly between individuals in a species. Beyond known roles for IL2 and TGFp, the mechanisms and genetic variation that control the selection and homeostatic balance of the Treg pool remain unclear. Following studies on the survival and homeostasis of "conventional" T cells in the previous cycle, we propose to build on our recent work that dissected the Treg transcriptional signature, established that the thymic differentiation and peripheral homeostasis of Treg cells are under independent genetic control, and showed that the extra-lymphoid localization of Treg cells are conditioned by TCR sub-repertoires and sub-phenotypes. We propose to study: 1) Cellular mechanisms of homeostatic control of Treg cells and their partners. We will continue to assess Treg population dynamics, also extending our results on extra-lymphoid populations, and in particular Treg cells which infiltrate the injured muscle and aid controlling its regeneration. We will also analyze the mechanisms of the interplay between Treg and NK cells in autoimmune lesions 2) Secondary conversion to Treg phenotype: significance and specificity. Neo-conversion of mature CD4* lymphocytes to a FoxP3+ state can be achieved by chronic antigen stimulation, lymphopenia-driven homeostatic expansion in vivo, or IL2+GFP in vitro. Secondary Treg differentiation may be important for tolerance to self or to gut flora, and is now well established. We are attempting to work out the specificity of these cells (in polyclonal settings, non- transgenic), in terms of TCR repertoire and of transcriptional signature, and as a function of variation in the gut microbiome. 3) Molecular determinism of Treg cell homeostasis. We will build upon our description of the Treg genetic switch, in which the Treg transcriptional signature can be stably switched on, in a self- reinforcing mode, by expression of FoxP3 and any of several co-factors. We will analyze in more detail the requirem^ints for this switch. We will explore the interactions of FoxPS with other TFs in this context, in particular in an RNAi screen which will probe the requirement for specific cofactors in this switch behavior.

Public Health Relevance

These experiments will explore the cellular mechanisms and regulatory pathways that lead to variations in the differentiation and homeostasis of FoxP3+ T regulatory cells. The results should lead to a better understanding of this population that is key to immune regulation, and impacts several autoimmune and inflammatory diseases.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI051530-12
Application #
8501762
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Lapham, Cheryl K
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Dépis, Fabien; Kwon, Ho-Keun; Mathis, Diane et al. (2016) Unstable FoxP3+ T regulatory cells in NZW mice. Proc Natl Acad Sci U S A 113:1345-50
Panduro, Marisella; Benoist, Christophe; Mathis, Diane (2016) Tissue Tregs. Annu Rev Immunol 34:609-33
Tan, Tze Guan; Mathis, Diane; Benoist, Christophe (2016) Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc Natl Acad Sci U S A 113:14103-14108
Sefik, Esen; Geva-Zatorsky, Naama; Oh, Sungwhan et al. (2015) MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells. Science 349:993-7
Yan, Dapeng; Farache, Julia; Mingueneau, Michael et al. (2015) Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3. Proc Natl Acad Sci U S A 112:14942-7
Magnuson, Angela M; Thurber, Greg M; Kohler, Rainer H et al. (2015) Population dynamics of islet-infiltrating cells in autoimmune diabetes. Proc Natl Acad Sci U S A 112:1511-6
Mingueneau, Michael; Krishnaswamy, Smita; Spitzer, Matthew H et al. (2014) Single-cell mass cytometry of TCR signaling: amplification of small initial differences results in low ERK activation in NOD mice. Proc Natl Acad Sci U S A 111:16466-71
Sitrin, Jonathan; Ring, Aaron; Garcia, K Christopher et al. (2013) Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J Exp Med 210:1153-65
Burzyn, Dalia; Kuswanto, Wilson; Kolodin, Dmitriy et al. (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155:1282-95
Burzyn, Dalia; Benoist, Christophe; Mathis, Diane (2013) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14:1007-13

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