TheBordetella pertussisadenylate cyclase toxin binds to T cells via LFA-1 and induces its disengagement from the immune synapse

Abstract

The Bordetella pertussis adenylate cyclase toxin (CyaA) assists infection by potently suppressing the host immune response. Although CyaA effectively targets T lymphocytes, its putative receptor on these cells is unknown. Here, we show that CyaA binds to T cells via the  2 integrin LFA-1 in its active conformation. CyaA clusters with LFA-1 at the immune synapse (IS), from which it induces the premature disengagement of LFA-1 concomitant with the dissipation of talin, which tethers the integrin to the underlying actin cytoskeleton. The CyaA-induced redistribution of LFA-1 was cAMP-and protein kinase A (PKA)-dependent. These results not only identify LFA-1 as a CyaA receptor on T cells but unveil a novel mechanism of immunosuppression whereby the toxin parasitizes its interaction with LFA-1 to inhibit signaling at the IS through the local production of cAMP. The data also provide novel insights into the role of cAMP/PKA signaling in controlling the dynamics of the IS.

Structure and function of RTX toxins

“…CyaA also induces K + efflux and Ca 2+ influx that contribute to the overall cytotoxicity of the toxin [283,284]. In addition, CyaA has been shown to affect the adaptive immune responses by altering the maturation of dendritic cells [301][302][303][304] and the activation (and chemotaxis) of T lymphocytes [305,306]. In the more general context of an infection, CyaA will not act alone, but more likely in synergy with the various pathogenic factors produced by B. pertussis [274,307,308].…”

“…Calcium triggers a calpain-mediated cleavage of talin that enables the β2 integrin-CyaA complex to cluster into lipid rafts, where the membrane translocation of the catalytic domain occurs. Interestingly, in T cells, CyaA induces a premature disengagement of LFA-1 from the immunological synapses in a cAMP-dependent manner [306]. These studies indicate that the cell biology of RTX toxins is likely to be more elaborate than initially thought.…”