title: T-cell co-stimulation through the CD2 and CD28 co-receptors induces distinct signalling responses.
abstract: Full T-cell activation critically depends on the engagement of the TCR (T-cell receptor) in conjunction with a second signal by co-stimulatory receptors that boost the immune response. In the present study we have compared signalling patterns induced by the two co-receptors CD2 and CD28 in human peripheral blood T-cells. These co-receptors were previously suggested to be redundant in function. By a combination of multi-parameter phosphoflow cytometry, phosphokinase arrays and Western blot analyses, we demonstrate that CD2 co-stimulation induces phosphorylation of the TCR-proximal signalling complex, whereas CD28 activates distal signalling molecules, including the transcription factors NF-κB (nuclear factor κB), ATF (activating transcription factor)-2, STAT3/5 (signal transducer and activator of transcription 3/5), p53 and c-Jun. These signalling patterns were conserved in both naïve and effector/memory T-cell subsets. We show that free intracellular Ca(2+) and signalling through the PI3K (phosphoinositide 3-kinase)/Akt pathway are required for proper CD28-induced NF-κB activation. The signalling patterns induced by CD2 and CD28 co-stimulation lead to distinct functional immune responses in T-cell proliferation and cytokine production. In conclusion, CD2 and CD28 co-stimulation induces distinct signalling responses and functional outcomes in T-cells.
authors.forename: Sigrid S
authors.initials: SS
authors.lastname: Skånland
authors.forename: Kristine
authors.initials: K
authors.lastname: Moltu
authors.affiliation: †Biotechnology Centre, K. G. Jebsen Centre for Inflammation Research and K. G. Jebsen Centre for Cancer Immunotherapy, University of Oslo, N-0318 Oslo, Norway.
authors.forename: Torunn
authors.initials: T
authors.lastname: Berge
authors.forename: Einar M
authors.initials: EM
authors.lastname: Aandahl
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D018801:CD2 Antigens / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology / Q000502:physiology*
chemical_list: D051698:Activating Transcription Factor 2; D018801:CD2 Antigens; D018106:CD28 Antigens; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium