CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as one of the key elements important for establishing and maintaining tolerance. While Treg have been the focus of much research, aspects of their basic physiology and function remain incompletely understood. In particular, it is not known where and when Treg or their precursors precisely interact with antigen, become activated, and deploy their suppressive regulatory mechanisms. The cellular and molecular mechanisms important for each of these steps are poorly delineated, and the migration and trafficking mechanisms essential for priming at one site and effector function in another site remain largely unknown. In the previous funding period, we published a number of important studies revealing that naive T cells migrate to lymph nodes (LN), where they are stimulated in the cortical area by specific alloantigen presenting plasmacytoid dendritic cells (pDC) to generate adaptive or induced Treg (aTreg). We elucidated several important molecular mechanisms in these interactions. In ongoing studies, we have made several additional key observations. First, while investigating the cell surface receptor signals and transcriptional factors that regulate Foxp3 expression, we have discovered that we can manipulate epigenetic regulation of the Foxp3 gene, through DNA methyltransferase (DNMT) inhibitors, to generate Treg. Second, in an islet transplant model we have discovered that nTreg migrate sequentially from the blood through microvascular endothelium into the site of tissue inflammation, and then subsequently from tissue into afferent lymphatics and then the draining LN (dLN), in order to be activated and fully display their suppressive functions. Sequential tissue and dLN migration are key components of nTreg physiology, and migration is coupled to developmental and differentiative steps. In contrast, aTreg precursors migrate first to the LN, and then to sites of inflammation. Third, Treg specifically express increased levels of lymphotoxin-? (LT?) on their cell surface;while endothelial cells, particularly lymphatic vascular endothelial cells, express increased levels of LT? receptor (LT?R). Inhibiting the LT?1?2-LT?R interaction inhibits Treg translymphatic migration, and inhibits tolerance to islet and cardiac allografts. Together these observations suggest that aTreg and nTreg have distinct requirements for migration, trafficking and suppressive function, and that these distinctions are critically important for immune suppression and regulation.

Public Health Relevance

The research will investigate and define the cellular and molecular interactions that are important for generating regulatory suppressor T cells and antigen specific tolerance. The ability to define these interactions and achieve tolerance is important for achieving good graft survival and patient survival for transplant recipients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062765-10
Application #
8463445
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2004-12-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$348,975
Indirect Cost
$116,325
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Tostanoski, Lisa H; Chiu, Yu-Chieh; Gammon, Joshua M et al. (2016) Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific. Cell Rep 16:2940-52
Brinkman, C Colin; Iwami, Daiki; Hritzo, Molly K et al. (2016) Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration. Nat Commun 7:12021
Lal, Girdhari; Kulkarni, Neeraja; Nakayama, Yumi et al. (2016) IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol Lett 170:52-63
Xiong, Yanbao; Ahmad, Sarwat; Iwami, Daiki et al. (2016) T-bet Regulates Natural Regulatory T Cell Afferent Lymphatic Migration and Suppressive Function. J Immunol 196:2526-40
Burrell, Bryna E; Warren, Kristi J; Nakayama, Yumi et al. (2015) Lymph Node Stromal Fiber ER-TR7 Modulates CD4+ T Cell Lymph Node Trafficking and Transplant Tolerance. Transplantation 99:1119-25
Harris, Anthony D; Fleming, Brandon; Bromberg, Jonathan S et al. (2015) Surgical site infection after renal transplantation. Infect Control Hosp Epidemiol 36:417-23
Iwami, Daiki; Brinkman, C Colin; Bromberg, Jonathan S (2015) Vascular endothelial growth factor c/vascular endothelial growth factor receptor 3 signaling regulates chemokine gradients and lymphocyte migration from tissues to lymphatics. Transplantation 99:668-77
Lal, Girdhari; Nakayama, Yumi; Sethi, Apoorva et al. (2015) Interleukin-10 From Marginal Zone Precursor B-Cell Subset Is Required for Costimulatory Blockade-Induced Transplantation Tolerance. Transplantation 99:1817-28
Nakayama, Yumi; Brinkman, C Colin; Bromberg, Jonathan S (2015) Murine Fibroblastic Reticular Cells From Lymph Node Interact With CD4+ T Cells Through CD40-CD40L. Transplantation 99:1561-7
Warren, Kristi J; Iwami, Daiki; Harris, Donald G et al. (2014) Laminins affect T cell trafficking and allograft fate. J Clin Invest 124:2204-18

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