title: Immature recent thymic emigrants are eliminated by complement.
abstract: Recent thymic emigrants (RTEs) must undergo phenotypic and functional maturation to become long-lived mature naive T cells. In CD4-cre NKAP conditional knockout mice, NKAP-deficient RTEs fail to complete T cell maturation. In this study, we demonstrate that NKAP-deficient immature RTEs do not undergo apoptosis, but are eliminated by complement. C3, C4, and C1q are bound to NKAP-deficient peripheral T cells, demonstrating activation of the classical arm of the complement pathway. As thymocytes mature and exit to the periphery, they increase sialic acid incorporation into cell surface glycans. This is essential to peripheral lymphocyte survival, as stripping sialic acid with neuraminidase leads to the binding of natural IgM and complement fixation. NKAP-deficient T cells have a defect in sialylation on cell surface glycans, leading to IgM recruitment. We demonstrate that the defect in sialylation is due to aberrant α2,8-linked sialylation, and the expression of three genes (ST8sia1, ST8sia4, and ST8sia6) that mediate α2,8 sialylation are downregulated in NKAP-defcient RTEs. The maturation of peripheral NKAP-deficient T cells is partially rescued in a C3-deficient environment. Thus, sialylation during T cell maturation is critical to protect immature RTEs from complement in the periphery.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Fan-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Meibo W
authors.initials: MW
authors.lastname: Chen
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: McWilliams
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Seaburg
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Tangen
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905 shapiro.virginia1@mayo.edu.
authors.forename: Virginia Smith
authors.initials: VS
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding / Q000276:immunology; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D018958:CD55 Antigens; D003176:Complement C3; D007075:Immunoglobulin M; C560431:NKAP protein, mouse; D012097:Repressor Proteins; C422908:Siglece protein, mouse; D003165:Complement System Proteins; D017493:Leukocyte Common Antigens; D019158:N-Acetylneuraminic Acid