title: Engagement of T-cell antigen receptor and CD4/CD8 co-receptors induces prolonged STAT activation through autocrine/paracrine stimulation in human primary T cells.
abstract: Signal transducer and activator of transcription (STAT) proteins are key signaling molecules in response to cytokines and in regulating T cell biology. However, there are contradicting reports on whether STAT is involved in T-cell antigen receptor (TCR) signaling. To better define the role of STAT in TCR signaling, we activated the CD4/CD8-associated Lck kinase by co-crosslinking TCR and CD4/CD8 co-receptors in human peripheral blood T cells. Sequential STAT1, STAT3 and STAT5 activation was observed 1 h after TCR stimulation suggesting that STAT proteins are not the immediate targets in the TCR complex. We further identified interferon-γ as the key cytokine in STAT1 activation upon TCR engagement. In contrast to transient STAT activation in cytokine response, this autocrine/paracrine-induced STAT activation was sustained. It correlated with the absence of two suppressors of cytokine signaling (SOCS) proteins, SOCS3 and cytokine-inducible SH2 containing protein that are negative feedback regulators of STAT signaling. Moreover, enforced expression of SOCS3 inhibited tyrosine phosphorylation of zeta-associated protein kinase of 70 kD in TCR-stimulated human Jurkat T cells. This is the first report demonstrating delayed and prolonged STAT activation coordinated with the loss of SOCS expression in human primary T cells after co-crosslinking of TCR and CD4/CD8 co-receptors.
authors.affiliation: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Fu-Yu
authors.initials: FY
authors.lastname: Chueh
authors.forename: Chao-Lan
authors.initials: CL
authors.lastname: Yu
mesh_terms: D019898:Autocrine Communication / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D019899:Paracrine Communication / Q000276:immunology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000819:agonists / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000819:agonists / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000819:agonists / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000819:agonists / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)