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Published on: August 16, 2019
Enhanced T cell function in a mouse model of human glycosylation
George Buchlis1, Pamela Odorizzi, Paula C Soto
1University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|May 28, 2013
Summary
Humans possess a unique genetic mutation affecting sialic acid expression, leading to a more active immune response. This human-specific trait, modeled in mice, results in enhanced T cell proliferation and immune activity, offering insights into human hyperimmune conditions.
Area of Science:
- Immunology
- Human Evolution
- Glycobiology
Background:
- Humans exhibit a more active immune response than chimpanzees, evidenced by diseases like AIDS and autoimmune disorders.
- A unique human mutation in the CMP-N-acetylneuraminic acid hydroxylase (CMAH) enzyme results in the loss of sialic acid Neu5Gc expression.
- This ancient mutation likely influenced sialic acid-binding receptors (Siglecs), impacting immune cell function.
Purpose of the Study:
- To investigate the functional consequences of the human-specific CMAH mutation on T cell activity.
- To determine if the loss of Neu5Gc expression directly impacts T cell proliferation and activation.
- To model the human immune phenotype in mice and assess T cell responses to viral infections.
Main Methods:
- Generated Cmah(-/-) knockout mice lacking Neu5Gc expression.
- Compared T cell proliferation and activation markers between Cmah(-/-) and wild-type mice.
- Administered Neu5Gc to Cmah(-/-) cells and mice to assess its effect on T cell responses.
- Evaluated T cell responses to adenovirus vectors and lymphocytic choriomeningitis virus (LCMV) infection in Cmah(-/-) mice.
Main Results:
- Cmah(-/-) mouse T cells showed increased proliferation and activation markers compared to wild-type.
- Metabolic reintroduction of Neu5Gc reduced T cell proliferation and activation in both human and mouse Cmah(-/-) cells.
- Cmah(-/-) mice mounted stronger T cell responses to adenovirus vectors and LCMV infection.
- These mice produced more polyfunctional virus-specific T cells.
Conclusions:
- The human-specific loss of Neu5Gc expression due to the CMAH mutation drives a more proliferative and active T cell population.
- This mouse model recapitulates key aspects of human immune activity, providing a valuable tool for studying immune responses.
- Findings have implications for understanding human hyperimmune diseases and developing novel therapeutic strategies.
