title: Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS.
abstract: During evolutionary adaptation in the immune system, host defense is traded off against autoreactivity. Signals through the costimulatory receptor CD28 enable T cells to respond specifically to pathogens, whereas those through the related costimulatory receptor, ICOS, which arose by gene duplication, are critical for affinity maturation and memory antibody responses. ICOS ligand, unlike the pathogen-inducible CD28 ligands, is widely and constitutively expressed in the immune system. Here, we show that crosstalk between these two pathways provides a mechanism for obviating the normal T cell dependence on CD28. Several CD28-mediated responses-generation of follicular helper T cells, germinal center formation, T helper 1 cell-dependent extrafollicular antibody responses to Salmonella and bacterial clearance, and regulatory T cell homeostasis-became independent of CD28 and dependent on ICOS when the E3 ubiquitin ligase Roquin was mutated. Mechanisms to functionally compartmentalize ICOS and CD28 signals are thus critical for two-signal control of normal immune reactions.
authors.affiliation: Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Linterman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rigby
authors.forename: Raphael
authors.initials: R
authors.lastname: Wong
authors.forename: Diego
authors.initials: D
authors.lastname: Silva
authors.forename: David
authors.initials: D
authors.lastname: Withers
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Verma
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Andreas
authors.initials: A
authors.lastname: Hutloff
authors.forename: Chris C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000483:Alleles; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D012475:Salmonella / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases