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BIOLOGICAL SCIENCES / IMMUNOLOGY
Loss of Siglec expression on T lymphocytes during human evolution
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*Glycobiology Research and Training Center and Departments of Medicine and Cellular and Molecular Medicine, and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093
Edited by Anthony S. Fauci, National Institutes of Health, Bethesda, MD, and approved April 3, 2006 (received for review December 5, 2005)
We report here that human T cells give much stronger proliferative responses to specific activation via the T cell receptor (TCR) than those from chimpanzees, our closest evolutionary relatives. Nonspecific activation using phytohemagglutinin was robust in chimpanzee T cells, indicating that the much lower response to TCR simulation is not due to any intrinsic inability to respond to an activating stimulus. CD33-related Siglecs are inhibitory signaling molecules expressed on most immune cells and are thought to down-regulate cellular activation pathways via cytosolic immunoreceptor tyrosine-based inhibitory motifs. Among human immune cells, T lymphocytes are a striking exception, expressing little to none of these molecules. In stark contrast, we find that T lymphocytes from chimpanzees as well as the other closely related "great apes" (bonobos, gorillas, and orangutans) express several CD33-related Siglecs on their surfaces. Thus, human-specific loss of T cell Siglec expression occurred after our last common ancestor with great apes, potentially resulting in an evolutionary difference with regard to inhibitory signaling. We confirmed this by studying Siglec-5, which is prominently expressed on chimpanzee lymphocytes, including CD4 T cells. Ab-mediated clearance of Siglec-5 from chimpanzee T cells enhanced TCR-mediated activation. Conversely, primary human T cells and Jurkat cells transfected with Siglec-5 become less responsive; i.e., they behave more like chimpanzee T cells. This human-specific loss of T cell Siglec expression associated with T cell hyperactivity may help explain the strikingly disparate prevalence and severity of T cell-mediated diseases such as AIDS and chronic active hepatitis between humans and chimpanzees.
chimpanzees | HIV/AIDS | T cells
D.H.N. and N.H.-Z. contributed equally to this work. ¶The term "great apes" is used in the colloquial sense; genomic information no longer supports this species grouping (38). Technically, these species are now grouped together with humans in the family Hominidae.
Author contributions: D.H.N., N.H.-Z., and A.V. designed research; D.H.N. and N.H.-Z. performed research; P.G. contributed new reagents/analytic tools; D.H.N., N.H.-Z., P.G., and A.V. analyzed data; and D.H.N., N.H.-Z., P.G., and A.V. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
To whom correspondence should be addressed. E-mail: a1varki{at}ucsd.edu
© 2006 by The National Academy of Sciences of the USA
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