Opposing roles for RhoH GTPase during T-cell migration and activation

Department of Microbiology and Immunology, David H Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2012; 109(26):10474-9. DOI: 10.1073/pnas.1114214109
Source: PubMed


T cells spend the majority of their time perusing lymphoid organs in search of cognate antigen presented by antigen presenting cells (APCs) and then quickly recirculate through the bloodstream to another lymph node. Therefore, regulation of a T-cell response is dependent upon the ability of cells to arrive in the correct location following chemokine gradients ("go" signal) as well as to receive appropriate T-cell receptor (TCR) activation signals upon cognate antigen recognition ("stop" signal). However, the mechanisms by which T cells regulate these go and stop signals remain unclear. We found that overexpression of the hematopoietic-specific RhoH protein in the presence of chemokine signals resulted in decreased Rap1-GTP and LFA-1 adhesiveness to ICAM-1, thus impairing T-cell chemotaxis; while in the presence of TCR signals, there were enhanced and sustained Rap1-GTP and LFA-1 activation as well as prolonged T:APC conjugates. RT-PCR analyses of activated CD4(+) T cells and live images of T-cell migration and immunological synapse (IS) formation revealed that functions of RhoH took place primarily at the levels of transcription and intracellular distribution. Thus, we conclude that RhoH expression provides a key molecular determinant that allows T cells to switch between sensing chemokine-mediated go signals and TCR-dependent stop signals.

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    • "Roles for both RhoA and RhoB have been identified in MHC II surface expression and antigen-dependent activation of T cells by DCs [135, 136]. RhoH, expressed specifically in hematopoietic lineage cells, is required for proper TCR signaling in thymocytes and mature T cells but suppresses chemokine-dependent adhesion [137-139]. However, Rho function is not restricted to T lymphocytes, as mast cells from RhoH-deficient mice display defects in degranulation and cytokine production [140]. "
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