We have questioned longstanding dogmas regarding the physiology and architecture of T-cell dependent area of lymph nodes, and evolved a much richer understanding by a combination of immunohistology, in vivo tracer studies, and cell culture. First, in the T-cell-dependent area T cells migrate in a highly organized labyrinth. The topology of that labyrinth is optimized for efficient cell contact: a) narrow aqueous channels lined b) by stromal cells rich in extracellular matrix suitable for providing traction for cell migration and c) by antigen-presenting interdigitating dendritic cells (IDC) specialized for presenting antigen. Second, there is an effective reticulo-endothelial cell barrier which isolates this compartment from the lymph/sinuses. Third, the movement of soluble tracers from lymph into the T cell dependent areas occurs by transport along an unprecedented conduit system ensheathed by the very stromal cells that form the walls of the labyrinth. Fourth, the stromal cells appear to condition the environment of the lymph node by producing their own soluble factors such as TGFb, and chemokines such as IL-8 and MCP-1. Understanding these features is important to treating diseases where immune responses are deficient (such as cancers) or exaggerated (such as arthritis and diabetes). Moreover, in initial in vitro studies, we find that lymph node stromal cells markedly facilitate T cell infection by HIV virus. We are investigating the morphological and biochemical processes whereby lymphocytes migrate, with particular emphasis on filopodia. We are systematically characterizing human and mouse peripheral blood subsets to understand the ensemble of surfaces molecules expressed by each. In general, better strategies will be required in the biological community to organize the mass of information on human proteins; we are developing an international resource which we designate PROW [Protein Reviews on the Web] to help address this problem.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009257-21
Application #
2463761
Study Section
Special Emphasis Panel (EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hao, Jian-Jiang; Wang, Guanghui; Pisitkun, Trairak et al. (2008) Enrichment of distinct microfilament-associated and GTP-binding-proteins in membrane/microvilli fractions from lymphoid cells. J Proteome Res 7:2911-27
Dong, Xiaoyun; Patino-Lopez, Genaro; Candotti, Fabio et al. (2007) Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation: evidence that WIP-WASP dissociation is not required and that the WIP NH2 terminus is inhibitory. J Biol Chem 282:30303-10
Liu, Yin; Kruhlak, Michael J; Hao, Jian-Jiang et al. (2007) Rapid T cell receptor-mediated SHP-1 S591 phosphorylation regulates SHP-1 cellular localization and phosphatase activity. J Leukoc Biol 82:742-51
Liu, Yin; Belkina, Natalya V; Graham, Caroline et al. (2006) Independence of protein kinase C-delta activity from activation loop phosphorylation: structural basis and altered functions in cells. J Biol Chem 281:12102-11
Zhu, Guozhi; Fujii, Koichi; Liu, Yin et al. (2005) A single pair of acidic residues in the kinase major groove mediates strong substrate preference for P-2 or P-5 arginine in the AGC, CAMK, and STE kinase families. J Biol Chem 280:36372-9
Sarkar, Kakali; Kruhlak, Michael J; Erlandsen, Stanley L et al. (2005) Selective inhibition by rottlerin of macropinocytosis in monocyte-derived dendritic cells. Immunology 116:513-24
Zhu, Guozhi; Fujii, Koichi; Belkina, Natalya et al. (2005) Exceptional disfavor for proline at the P + 1 position among AGC and CAMK kinases establishes reciprocal specificity between them and the proline-directed kinases. J Biol Chem 280:10743-8
Zhu, Guozhi; Liu, Yin; Shaw, Stephen (2005) Protein kinase specificity. A strategic collaboration between kinase peptide specificity and substrate recruitment. Cell Cycle 4:52-6
Anderson, Arthur O; Shaw, Stephen (2005) Conduit for privileged communications in the lymph node. Immunity 22:3-5
Salganik, M P; Milford, E L; Hardie, D L et al. (2005) Classifying antibodies using flow cytometry data: class prediction and class discovery. Biom J 47:740-54

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