Autonomous induction of proliferation, JNK and NF-κB activation in primary resting T cells by mobilized CD28

Abstract

Induction of proliferation in primary resting T cells requires engagement of both the antigen‐specific TCR and the co‐stimulatory receptor CD28. Here we report that CD28 functions as an autonomous mitogenic receptor which is mobilized by TCR signaling through cytoskeletal rearrangement. Shortcutting of TCR‐dependent CD28 recruitment by stimulation with monoclonal antibodies specific for mobilized CD28 results in maximum proliferation and IL‐2 secretion in primary resting T cells without activation of ZAP‐70, a central component of the TCR's signal transduction machinery. Engagement of mobilized CD28 fully activates the c‐Jun N‐terminal kinase cascade and translocation of NF‐κB, two key targets of signal integration in co‐stimulation. We propose a two‐step activation model for co‐stimulation in primary resting T cells in which antigen recognition recruits co‐stimulatory receptors which then autonomously transduce signals promoting T cell proliferation.

Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways

“…2–4, 6). This phenomenon resembles previous data on the mechanisms of CD28 costimulation, pointing to JNK as a key molecule in the integration of TCR and CD28 signals for secretion of lymphokines like IL‐2 23, 26, although recent data challenges JNK as the sole integration point of TCR and CD28 39, 40, 42. Furthermore, integration of TCR and CD28 signals can also occur at Vav and ZAP‐70, upstream in the activation cascade 22, 24, 25, 28.…”

A recombinant bispecific single‐chain antibody induces targeted, supra‐agonistic CD28‐stimulation and tumor cell killing

“…On the other hand, antibodies directed to rat CD28 have been described that induce maximalT cell proliferation in vitro and in vivo without additional TCR/CD3 triggering. This activity has been attributed to the peculiar specificity of such antibodies for "mobilized" CD28, which shortcuts TCR‐dependent CD28 recruitment 22. With human T cells, moderate TCR/CD3‐independent activation was observed using a particular immobilized CD28 antibody, BW828.…”

CD28 Superagonists: What Makes the Difference in Humans?

“…According to the above paradigm, these reagents support T cell activation only in combination with a primary, TCR-mediated, stimulus (e.g., provided by TCR antibodies). Approximately ten years ago, a new group of CD28 antibodies, now called CD28 superagonists (CD28SA) or mitogenic CD28 mAbs, has been described (Bischof et al, 2000;Dennehy et al, 2007;Dennehy et al, 2003;Tacke et al, 1997). In contrast to conventional CD28 antibodies, CD28 superagonists are capable of triggering the activation of rat, mouse, and human T lymphocytes upon binding to CD28 alone.…”

“…For instance, signaling via both anti-rat and anti-human CD28SAs depends on Src-family protein tyrosine kinases and activation of the SLP76 signalosome (which is required for inducing transmembranous calcium flux and consists of the adaptor protein SLP76, the nucleotide exchange factor Vav, the Teckinase Itk, and phospholipase Cg). Further, anti-rat and anti-human CD28SAs activate protein kinase Cq and ras and Erk kinases, as well as the transcription factors NF-ATc1 and NF-kB (Bischof et al, 2000;Dennehy et al, 2003;Sester et al, 2007;Waibler et al, 2008). How all these signals are initiated at the plasma membrane is still not completely understood.…”