RhoH is a key functional determinant of the “stop and go” nature of CD4+ T cells during activation (109.17)

Abstract

Abstract CD4+ T cells spend the majority of their time perusing lymphoid organs in search of cognate antigen presented by APCs, and then cells quickly recirculate through the bloodstream to another lymph node. Therefore regulation of a CD4+ T cell response is dependent upon the ability of cells to arrive in the correct location following chemokine gradients (“go” signals) as well as to receive appropriate TCR activation signals upon cognate antigen recognition (“stop” signals). The mechanism(s) by which a CD4+ T cell regulates these “go” and “stop” signals are not well defined. We find that over-expression of the hematopoietic specific RhoH protein in the presence of chemokine signals results in decreased Rap1-GTP and LFA-1 adhesiveness to ICAM-1, thus impairing T cell chemotaxis, while in the presence of TCR signals there is enhanced and sustained Rap1-GTP and LFA-1 activation as well as prolonged T:APC conjugates. RhoH-/- CD4+ T cells appear to circulate through the blood and lymphoid tissue more quickly corroborating our in vitro migration data. RT-PCR analyses of activated CD4+ T cells and live images of T cell migration and immunological synapse formation have revealed that functions of RhoH take place primarily at the levels of transcription and intracellular distribution. Thus, we hypothesize that RhoH expression may provide a single molecular determinant that allows a CD4+ T cell to switch between sensing chemokine mediated “go” signals and TCR dependent “stop” signals.