Achieving tolerance remains the most important goal in transplantation immunology. Models of tolerance employing co-stimulatory blockade are among the most robust and clinically relevant approaches. Much is known about the mechanisms of tolerance that are operative during co-stimulatory blockade, such as anergy, apoptosis, and regulatory T cells (Treg). However, it is often difficult to induce and maintain robust tolerance that is resistant to external perturbations. This suggests that other important immunologic mechanisms that determine tolerance remain to be elucidated. Our laboratory has focused on the role of migration, trafficking and secondary lymphoid organ structure as crucial regulatory processes that determine whether immune interactions result in immunity versus tolerance. In several key publications we demonstrated that tolerance is initiated in lymph nodes (LN) through the precise interaction of specific alloantigen presenting cells with na?ve antigen specific T cells to generate regulatory suppressive T cells. This interaction occurs in the LN, and is dependent on the intricate coordination of many molecular signals. Subsequent trafficking of the suppressive T cells is critical, so that migration from blood to grafts and then into lymphatic has distinct and unique suppressive effects, in comparison to migration through blood and LNs. We have elucidated several novel and unexpected mechanisms that are required for tolerance induction, and these mechanisms relate to the interaction of LN structure with the cellular and molecular mechanisms of lymphocyte responses. The results demonstrate that T cells destined to become suppressors are found in only one region of the LN, called the cortical ridge. In contrast, T cells destined to become effectors are found scattered throughout the LN. The cortical ridge is particularly rich in specialized fibers and stromal cells, called fibroblastic reicular cells (FRC), suggesting a unique function or arrangement for these cells and their associated fibers. Together these observations lead to the hypothesis that the LN domain of the cortical ridge, that encompasses the HEV and their surrounding stromal fibers, is a major locus for tolerization. During tolerization na?ve T cells and alloantigen presenting pDC enter this domain and remain around the HEV within the stromal fibers. Precise stromal cell function and fiber arrangement are required to create and maintain the microenvironment necessary for Treg induction. These Treg persist in this high-traffic region and act as gatekeepers for new T cells that traverse the HEV. These Treg regulate the migration, activation, and fate of new na?ve antigen specific T cells as they enter the LN, and thus the Treg determine tolerance or immunity.

Public Health Relevance

Achieving tolerance remains the most important goal in transplantation. The significance of the current proposal is that it will define for the first timethe function and mechanisms of specialized cells and structures in the lymph node that determine transplantation tolerance, and how they determine the choice between immunity versus tolerance. The findings from these investigations will have general applicability to other areas of immunology such as infection, vaccination, and autoimmunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Kehn, Patricia J
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University of Maryland Baltimore
Schools of Medicine
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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
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
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
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
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
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
Yin, Na; Zhang, Nan; Xu, Jiangnan et al. (2011) Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation 92:25-30
Lal, Girdhari; Bromberg, Jonathan S (2009) Epigenetic mechanisms of regulation of Foxp3 expression. Blood 114:3727-35

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