Dephosphorylation of pp19: a common second signal for human T cell activation mediated through different accessory molecules

Abstract

Accessory molecules are thought to provide essential regulatory signals for T cell activation. In order to identify specific intracellular events linked to triggering through accessory surface receptors, mAbs against CD2, CD3, CD4, and CD8 were employed to activate resting human T lymphocytes in vitro. Subsequently, intracellular phosphorylation of phosphoprotein (pp) 19, a recently identified substrate of a serine phosphatase involved in CD2 mediated T cell triggering, as well as functional parameters (responsiveness to IL-6, production of IL-2 and IFN-gamma) were determined. As in responses to CD2 mAbs, cross-linking of CD4 and/or CD8 to the TCR-CD3 complex but not CD3 cross-linking alone promoted pp19 dephosphorylation. This early event was in all cases followed by particular late functional responses, i.e. induction of IL-6 responsiveness and secretion of IL-2. In marked contrast, no relationship was found between pp19 dephosphorylation and IFN-gamma production. Taken together, a common intracellular pathway appears to exist in which signals mediated through CD2, CD4, and CD8 merge to promote monokine responsiveness and IL-2 production in human T cells. Dephosphorylation of pp19 thus appears to represent a process which is linked to critical 'second signals' involved in the generation of antigen induced T cell responses.

T-cell-receptor-dependent actin regulatory mechanisms

“…In resting human peripheral blood T cells, cofilin exists in its inactive Ser3-phosphorylated form. Co-stimulation of the TCR together with the co-receptors CD2 or CD28, but not TCR triggering alone, induces dephosphorylation of cofilin, resulting in its activation (Samstag et al, 1994;Samstag et al, 1992). Since co-stimulation contributes decisively to sustained actin dynamics at the T-cell-APC contact zone (TskvitariaFuller et al, 2003), activation of cofilin may represent a key mechanism by which co-stimulatory signaling promotes T-cell activation (Samstag et al, 2003).…”

Ras/PI3Kinase/cofilin‐independent activation of human CD45RA+ and CD45RO+ T cells by superagonistic CD28 stimulation

“…In quiescent T cells, cofilin is constitutively phosphorylated on Ser3. Costimulation leads to its dephosphorylation [4,6], which is mediated via the small GTPase Ras and its downstream effector PI3Kinase [7]. Cofilin dephosphorylation enables its binding to actin.…”

Cofilin peptide homologs interfere with immunological synapse formation and T cell activation

“…In resting peripheral blood T lymphocytes (PBT), cofilin is mainly phosphorylated at serine 3 and inactive. After costimulation via accessory receptors (e.g., CD2 or CD28) but not on TCR engagement alone, cofilin is activated through dephosphorylation (17,20,21). Activated cofilin transiently associates with the actin cytoskeleton (18).…”