Enhanced T cell function in a mouse model of human glycosylation

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Buchlis, G; Odorizzi, P; Soto, PC; Pearce, OM; Hui, DJ; Jordan, MS; Varki, A; Wherry, EJ; High, KA
Year of Publication: 2013
Journal: Journal of Immunology
Volume: 191
Edition: 2013/05/28
Number: 1
Pagination: 228-37
Date Published: Jul 1
Type of Article: Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't
Publication Language: eng
ISBN Number: 1550-6606 (Electronic)00
Accession Number: 23709682
Keywords: Animals, CD4-Positive T-Lymphocytes/immunology/metabolism/virology, Cell Proliferation, Cells, Cultured, Dependovirus/genetics/immunology/metabolism, Glycosylation, Humans, Lymphocyte Activation/*genetics/*immunology, Lymphocytic choriomeningitis virus/ge
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.

Notes:

J Immunol. 2013 Jul 1;191(1):228-37. doi: 10.4049/jimmunol.1202905. Epub 2013 May 24.

Custom 2:

3691298

Author Address:

University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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