Fibroblastic reticular cells (FRCs), one of the major populations of non-hematopoietic stromal cells in lymph node (LNs), secrete extracellular matrix components to form a dense reticular network and lymph-draining conduit system. The T cell zone is delineated by FRCs, forming a scaffold to provide essential guidance cues to immune cells. FRCs orchestrate immune cell migration via expression of CCL19 and CCL21, as well as adhesion molecules, integrins, and glycoproteins. Beyond migration, FRCs maintain na?ve T cell homeostasis and they have the capacity to impose antigen-specific deletional tolerance, with direct presentation of viral and self-peptides to na?ve CD8+ T cells. The timing of deletional events in these studies, whether an inevitable outcome of an FRC-mediated activation signal to na?ve T cells, or a result of subsequent feedback to the FRC from the activated T cell, is unknown, as are its driving molecular mechanisms. Additionally, in the context of immune response, T cells are usually activated by dendritic cells (DCs) while in direct contact with the FRC network, therefore any effect of FRCs on activated T cells is highly relevant. Our recent studies suggest that FRCs can acquire suppressive function at different stages in the T cell response;this newly appreciated function of FRCs appears to control the expansion of potentially pathogenic T cells via a NOS2-dependent mechanism. This project aims to further define the molecular and physical basis of the interactions between activated T cells and FRCs within lymph nodes. Despite recent advances indicating that stromal determinants of secondary lymphoid organs exhibit complex regulatory roles during immune responses, our knowledge of the stromal niche and how it impacts T cell immunity and tolerance is limited. The proposed studies will define the molecular crosstalk that culminates in CD8 T cell suppression by FRCs. They will also establish the influence of FRCs on the positioning and motility of activated T cells Finally, these studies will determine the capacity of FRCs to present lymph-borne antigen to CD4 T cells. The results of these studies will elucidate the molecular and physical interactions between lymph node FRCs and newly activated CD8 and CD4 T cells, and the role of FRCs in patrolling the lymph by sampling antigens from the conduit system, and the impact of inflammation on these processes.

Public Health Relevance

Emerging evidence suggests that stromal determinants of secondary lymphoid organs exhibit complex regulatory roles during immune responses. We recently described a novel in vivo cross-talk between activated T cells and fibroblastic reticular cells (FRCs) that endows these stromal cells with the capacity to constrain the proliferation of activated T cells through regulated nitric oxide (NO) release. The over-arching goal of this proposal is to further elucidate the molecular and physical basis of FRC-T cell cross-talk. This work may provide critical insights for the development of new therapeutic strategies to treat human inflammatory and autoimmune diseases associated with unbridled T cell immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074500-07
Application #
8534095
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Spain, Lisa M
Project Start
2006-04-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$352,549
Indirect Cost
$142,661
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Fletcher, Anne L; Elman, Jessica S; Astarita, Jillian et al. (2014) Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis. Sci Transl Med 6:249ra109
Elpek, Kutlu G; Cremasco, Viviana; Shen, Hua et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2:655-67
Cremasco, Viviana; Woodruff, Matthew C; Onder, Lucas et al. (2014) B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat Immunol 15:973-81
Malhotra, Deepali; Fletcher, Anne L; Turley, Shannon J (2013) Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity. Immunol Rev 251:160-76
Malhotra, Deepali; Fletcher, Anne L; Astarita, Jillian et al. (2012) Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol 13:499-510
Lv, Huijuan; Havari, Evis; Pinto, Sheena et al. (2011) Impaired thymic tolerance to ýý-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121:1561-73
Lukacs-Kornek, Veronika; Turley, Shannon J (2011) Self-antigen presentation by dendritic cells and lymphoid stroma and its implications for autoimmunity. Curr Opin Immunol 23:138-45
Lukacs-Kornek, Veronika; Malhotra, Deepali; Fletcher, Anne L et al. (2011) Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol 12:1096-104
Elpek, Kutlu G; Bellemare-Pelletier, Angelique; Malhotra, Deepali et al. (2011) Lymphoid organ-resident dendritic cells exhibit unique transcriptional fingerprints based on subset and site. PLoS One 6:e23921
Fletcher, Anne L; Malhotra, Deepali; Turley, Shannon J (2011) Lymph node stroma broaden the peripheral tolerance paradigm. Trends Immunol 32:12-8

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