Nuclear calcium is required for human T cell activation.
Calcium signals in stimulated T cells are generally considered single entities that merely trigger immune responses, whereas costimulatory events specify the type of reaction. Here we show that the "T cell calcium signal" is a composite signal harboring two distinct components that antagonistically control genomic programs underlying the immune response. Using human T cells from healthy individuals, we establish nuclear calcium as a key signal in human T cell adaptogenomics that drives T cell activation and is required for signaling to cyclic adenosine monophosphate response element-binding protein and the induction of CD25, CD69, interleukin-2, and γ-interferon. In the absence of nuclear calcium signaling, cytosolic calcium activating nuclear factor of activated T cells translocation directed the genomic response toward enhanced expression of genes that negatively modulate T cell activation and are associated with a hyporesponsive state. Thus, nuclear calcium controls the T cell fate decision between a proliferative immune response and tolerance. Modulators of nuclear calcium-driven transcription may be used to develop a new type of pro-tolerance immunosuppressive therapy.
Interdisciplinary Center for Neurosciences, Department of Neurobiology, Heidelberg University, 69120 Heidelberg, Germany.
Sara
http://orcid.org/0000-0001-7229-7075
S
Monaco
Institute of Immunology, Section Molecular Immunology, Heidelberg University, 69120 Heidelberg, Germany.
Beate
http://orcid.org/0000-0002-5697-4977
B
Jahraus
Institute of Immunology, Section Molecular Immunology, Heidelberg University, 69120 Heidelberg, Germany.
Yvonne
Y
Samstag
Interdisciplinary Center for Neurosciences, Department of Neurobiology, Heidelberg University, 69120 Heidelberg, Germany bading@nbio.uni-heidelberg.de.
Hilmar
H
Bading
D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D015415:Biomarkers; C497410:CREM protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D051786:Cyclic AMP Response Element Modulator; D002118:Calcium