title: Enhanced T cell function in a mouse model of human glycosylation.
abstract: Clinical evidence for a more active immune response in humans compared with our closest hominid relative, the chimpanzee, includes the progression of HIV infection to AIDS, hepatitis B- and C-related inflammation, autoimmunity, and unwanted harmful immune responses to viral gene transfer vectors. Humans have a unique mutation of the enzyme CMP-N-acetylneuraminic acid hydroxylase (CMAH), causing loss of expression of the sialic acid Neu5Gc. This mutation, occurring 2 million years ago, likely altered the expression and function of ITIM-bearing inhibitory receptors (Siglecs) that bind sialic acids. Previous work showed that human T cells proliferate faster than chimpanzee T cells upon equivalent stimulation. In this article, we report that Cmah(-/-) mouse T cells proliferate faster and have greater expression of activation markers than wild-type mouse T cells. Metabolically reintroducing Neu5Gc diminishes the proliferation and activation of both human and murine Cmah(-/-) T cells. Importantly, Cmah(-/-) mice mount greater T cell responses to an adenovirus encoding an adeno-associated virus capsid transgene. Upon lymphocytic choriomeningitis virus infection, Cmah(-/-) mice make more lymphocytic choriomeningitis virus-specific T cells than WT mice, and these T cells are more polyfunctional. Therefore, a uniquely human glycosylation mutation, modeled in mice, leads to a more proliferative and active T cell population. These findings in a human-like mouse model have implications for understanding the hyperimmune responses that characterize some human diseases.
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: George
authors.initials: G
authors.lastname: Buchlis
authors.forename: Pamela
authors.initials: P
authors.lastname: Odorizzi
authors.forename: Paula C
authors.initials: PC
authors.lastname: Soto
authors.forename: Oliver M T
authors.initials: OM
authors.lastname: Pearce
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase