Conditions of limited calcium influx (CLCI) inhibits IL2 induction and favors expression of anergy-related genes in TCR/CD3 and CD28 costimulated primary human T cells. (October 2019)

• Record Type: Journal Article
• Authors: Monaco, Sara; Jahraus, Beate; Samstag, Yvonne; Bading, Hilmar
• Is Part Of: Molecular immunology. Volume 114(2019:Oct.)
• Page Start: 81
• Page End: 87
• Publication Date: 2019-10
• Subjects: CLCI conditions of limited calcium influx -- qRT-PCR quantitative reverse transcriptase PCR -- NFAT nuclear factor of activated T cell -- CaM calmodulin -- IL2 Interleukin 2 -- EGR3 Early growth response 3 -- CREM cAMP response element modulator -- TCR T cell receptor -- CRAC calcium-release-activated calcium -- SOCE Store Operated Calcium Entry; T cell activation -- Gene expression -- Anergy-related genes -- Calcium -- IL2 -- NFAT2; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2019.07.006
• Languages: English
• ISSNs: 0161-5890

Abstract

Graphical abstract: Highlights: Induction of activation vs anergy-related genes in human T cells have different requirements for transmembrane calcium flux. EGTA or ORAI blockers allow for generation of conditions of limited calcium influx (CLCI). CLCI blocks IL2 expression and favors expression of anergy-related genes in activated human T cells. CLCI do not block NFAT translocation. CLCI may be exploited for the development of pro-tolerance immunosuppressive therapies. Abstract: Calcium is a key regulator of the T cell immune response. Depending on the spatial properties (nucleus versus cytoplasm) of the calcium signals generated after CD3xCD28 stimulation, primary human T cells either mount a productive immune response or develop tolerance. Nuclear calcium acts as a genomic decision maker: during T cell activation, it drives expression of genes associated with a productive immune response while in its absence, stimulated T cells acquire an anergy-like gene profile. Selective inhibition of nuclear calcium signaling in stimulated T cells blocks the productive immune response and directs the cells towards an anergy-like state. Here we show that the two transcriptional programs that include, respectively, the 'activation gene', interleukin 2 ( IL2 ) and 'anergy-related genes', EGR2, EGR3, and CREM have different requirements for transmembrane calcium flux. By either lowering extracellular calcium concentrations with EGTA or using low concentrations of the ORAI blockers, BTP2 or RO2959, we reduced transmembrane calcium flux in human primary T cells stimulated with CD3xCD28. These 'conditions of limited calcium influx' (CLCI) blocked CD3xCD28-induced IL2 expression but only moderately affected induction of the anergy-related genes EGR2, EGR3, and CREM . We observed no difference in NFAT2 nuclear translocation after CD3xCD28 stimulation between normal conditions and CLCI. These results indicate that CLCI favors expression of anergy-related genes in activated human T cells. CLCI may be used to develop novel means for pro-tolerance immunosuppressive treatments.