Back in 2006, a study published in PNAS suggested that chimpanzees may be relatively resistant to AIDS due to proteins called Siglecs (sialic acid-recognizing Ig-super family lectins). Siglecs are involved in downregulating innate immune activation and the PNAS study, authored by Dzung Nguyen and colleagues, showed that chimpanzee T cells express Siglecs while human T cells do not. The study further showed that Siglec expression appeared to make chimpanzee T cells less sensitive to CD3-mediated activation, offering a potential explanation of why the animals rarely develop immune activation (and, ultimately, AIDS) as a result of HIV infection.
Now, a new paper in J. Virology raises a caveat regarding the interpretation of these data. It turns out that the antibody used to stimulate T cells in the PNAS study, dubbed UCHT1, may be intrinsically less able to stimulate chimpanzee T cells compared to other anti-CD3 antibodies. The authors of the new paper, led by Frederic Bibollet-Ruche, show that the activation of human and chimpanzee T cells is far more comparable when a different anti-CD3 antibody (OKT3) is used. These differences are explained by the fact that the two antibodies belong to different isotypes; UCHT1 is an IgG1 antibody but OKT3 is IgG2a.
While chimpanzee T cells still appeared somewhat less efficiently activated even with OKT3, the authors emphasize that the optimal conditions for activating these cells in vitro remains unknown and needs to be resolved in order for future comparisons to be made with any confidence (they note, for example, that the use of anesthesia and restraint prior to sampling could impact the functional profile of the T cells).
JVI Accepts, published online ahead of print on 30 July 2008
J. Virol. doi:10.1128/JVI.01319-08
Frederic Bibollet-Ruche, Brett A. McKinney, Alexandra Duverger, Frederic H. Wagner, Aftab A. Ansari, and Olaf Kutsch
Departments of Medicine and Genetics, The University of Alabama at Birmingham, Birmingham, AL; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
While HIV-1 infection is associated with hyper-immune activation and systemic depletion of CD4+ T cells, SIV infection in sooty mangabeys or chimpanzees does not exhibit these hallmarks. Control of immune activation is thought to be one of the major components that govern species dependent differences in the disease pathogenesis. A previous study introduced the idea that the resistance of chimpanzees to SIVcpz infection induced hyper-immune activation could be the result of the expression of select sialic acid recognizing Ig-super family lectins (Siglec) by chimpanzee T cells. Siglecs, which are absent on human T cells, were reasoned to control levels of T cell activation in chimpanzees and thus suggested to account for the pathogenic differences in the course of SIVcpz or HIV-1 infection. As in human models of T cell activation, stimulation had been attempted using an anti-CD3 monoclonal antibody (mAb) (UCHT1; IgG1), but despite efficient binding, UCHT1 failed to activate chimpanzee T cells, an activation block that could be partially overcome by mAb-induced Siglec-5 internalization. We herein demonstrate that anti-CD3 mAb-mediated chimpanzee T cell activation is a function of the anti-CD3 mAb isotype and is not governed by Siglec expression. While IgG1 anti-CD3 mAbs fail to stimulate chimpanzee T cells, IgG2a anti-CD3 mAbs activate chimpanzee T cells in the absence of Siglec manipulations. Our results thus imply that prior to studying possible differences between human and chimpanzee T cell activation, a relevant model of chimpanzee T cell activation needs to be established.
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