Lymphoid tissue inducer (LTi) cells represent a rare hematopoietic cell lineage that has emerged as a key regulator of lymphoid tissue homeostasis. LTi cells were originally identified as an essential cell that initiates the embryonic formation of secondary lymphoid organs, including lymph nodes and intestinal Peyer's patches. This distinct lineage of cells persists in the adult and appears to play a critical role in the homeostasis of lymphoid organs following inflammatory responses. LTi cells are also implicated in formation of tertiary lymphoid aggregates at sites of chronic inflammation, and may be critical for controlling dendritic cell proliferation. LTi cells are extremely rare, typically less than 0.5% cells in the adult mouse spleen, making investigation into their function extremely difficult. Almost nothing is known about the LTi lineage in humans and their role in immune function. The lack of culture systems to grow these cells in pure populations has severely hampered investigations into the function of LTi cells. We have recently isolated human LTi from peripheral blood using high speed cell sorting, and identified culture conditions that allow LTi to survive, expand and differentiate in response to cytokine signals. The cultured, putative human LTi cells respond to IL-7 by induction of lymphotoxin (LT)-? and CD30 ligand, key cytokines required for lymphoid homeostasis and immune memory. IL7 also induced IL17A and RORc implicating expansion of adult human LTi cells with gene expression profile similar to mouse LTi cells. This discovery will allow assessment of the role of LTi cells in immune responses and identify new strategies in treating disease. To accomplish this goal we will characterize the gene expression patterns of human LTi cells in response to cytokines, and with pure population of cells determine their immune regulatory properties.

Public Health Relevance

Our research has isolated a rare human white blood cell with characteristics that may be important in regulating immune responses to pathogens. We have developed a culture method that allows these cells to grow, which will aid us in identifying genes that may be unique to these cells, and provide molecular identity of this cell to study in human infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AI088445-02
Application #
8136779
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2010-08-01
Project End
2012-01-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$171,864
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bekiaris, Vasileios; Ĺ edy, John R; Rossetti, Maura et al. (2013) Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-?? and are elevated in rheumatoid arthritis. J Immunol 191:4611-8
Sato-Hashimoto, Miho; Saito, Yasuyuki; Ohnishi, Hiroshi et al. (2011) Signal regulatory protein ? regulates the homeostasis of T lymphocytes in the spleen. J Immunol 187:291-7
Steinberg, Marcos W; Cheung, Timothy C; Ware, Carl F (2011) The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev 244:169-87
Ware, Carl F; Sedy, John R (2011) TNF Superfamily Networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14). Curr Opin Immunol 23:627-31
Vonarbourg, Cedric; Mortha, Arthur; Bui, Viet L et al. (2010) Regulated expression of nuclear receptor ROR?t confers distinct functional fates to NK cell receptor-expressing ROR?t(+) innate lymphocytes. Immunity 33:736-51