Despite the detailed understanding of signals 1, 2, and 3 and the critical function of T cells and dendritic cells (DC), clinical transplantation tolerance is almost never achieved. In transplantation, models of immune function, and interventions designed to promote immune regulation, have been based on simplified receptor-ligand and cell-cell interaction models. There has been a lack of studies that place immunological recognition within anatomic contexts and evaluate the critical role of anatomic microdomains in the regulation of the immune response. Our preliminary data now demonstrate that during tolerization there is alloantigen specific clustering of T cells and plasmacytoid DC (pDC) in the T cell areas of the lymph node (LN) near the abluminal surface of the high endothelial venules (HEV). Within these clusters T cells undergo either priming or development into de novo CD4+CD25+ regulatory T cells (Treg). Importantly, B cells presenting specific alloantigen are present in these cell clusters and contribute to Treg development. We hypothesize these multicellular clustered interactions in the LN are key to the induction and maintenance of tolerance. Specifically, we hypothesize that the precise interaction of T-APC (pDC, B cells) determines the outcome of T cell migration, positioning, proliferation, and maturation, and ultimately whether rejection or tolerance are induced. This hypothesis integrates many of the known receptor-ligand and cell-cell interactions, and places these interactions in the context of secondary lymphoid organ structure. To investigate the role of these cellular and structural elements in LN clustered interactions, we propose the following specific aims:
Specific Aim 1. What are the T-APC-LN interactions that are important for tolerance? Using a transplant model that allows the tracking of alloantigen specific T cells, specific alloantigen presenting APC, and the positioning of the cells with respect to HEV, we will characterize specific receptor-ligand interactions between T-HEV and pDC-HEV that regulate tolerance, and define the interactions between T-pDC and other DC that determine the generation of Treg and inhibition of effector T cells within the LN.
Specific Aim 2. How is the priming of effector T cells altered in the LN during tolerance? This aim will study the specific interaction between effector T cells and Treg in the LN clusters during tolerization. We will determine how Treg-T effector interactions regulate effector T cell migration, proliferation, and differentiation. We will characterize specific receptor-ligand interactions between Treg and T effector cells that determine whether T cell priming and rejection versus suppression and tolerance predominate in the immune response.
Specific Aim 3. Determine the role of B cells in tolerance in the LN We will investigate the roles of B cells in the LN during the T-APC clustered interaction that results in tolerization. Analyses will focus on B cell APC function, chemokine production, and immunoglobulin production.

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Kehn, Patricia J
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University of Maryland Baltimore
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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
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
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
Pierson 3rd, Richard N; Bromberg, Jonathan S (2015) Alloantibodies and Allograft Arteriosclerosis: Accelerated Adversity Ahead? Circ Res 117:398-400
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
Brinkman, C Colin; Burrell, Bryna E; Iwami, Daiki et al. (2013) Anatomy of tolerance. Curr Opin Organ Transplant 18:393-401
Burrell, B E; Bromberg, J S (2012) Fates of CD4+ T cells in a tolerant environment depend on timing and place of antigen exposure. Am J Transplant 12:576-89

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