The Quality of Chimpanzee T-Cell Activation and Simian Immunodeficiency Virus/Human Immunodeficiency Virus Susceptibility Achieved via Antibody-Mediated T-Cell Receptor/CD3 Stimulation Is a Function of the Anti-CD3 Antibody Isotype

Abstract

While human immunodeficiency virus type 1 (HIV-1) infection is associated with hyperimmune activation and systemic depletion of CD4؉ T cells, simian immunodeficiency virus (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 hyperimmune activation could be the result of the expression of select sialic acid-recognizing immunoglobulin (Ig)-like lectin (Siglec) superfamily members by chimpanzee T cells. Siglecs, which are absent on human T cells, were thought to control levels of T-cell activation in chimpanzees and were thus suggested as a cause 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; isotype 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.

Relative Over-Reactivity of Human versus Chimpanzee Lymphocytes: Implications for the Human Diseases Associated with Immune Activation

“…This dose response parallels previous findings, which showed that chimpanzee T cells were able to proliferate in response to anti-CD3 Abs, but to a lesser degree than human T cells at the doses tested (56). We even found one anti-CD3 Ab clone, SK7, which results only in human but not chimpanzee T cell proliferation, despite high doses tested (Table I).…”

“…However, as the dose of anti-CD3 was increased, chimpanzee T cells were eventually able to respond equally. This finding is independent of the binding affinity of the anti-CD3 Abs to human and chimpanzee T cells, which was found to be comparable by flow cytometry (data not shown), and is consistent with the sequences of the CD3ε ectodomain, the subunit recognized by anti-CD3 Abs, that are known to be identical in human and chimpanzee but for a single serine-glycine substitution at 68 aa (56). In addition, this is independent of the levels of expression of CD28 on human and chimpanzee T cells, which has previously been shown to be similar (39).…”

“…Both clone SK7 and clone UCHT1 are isotype IgG1. This result indicates that these differences are not in fact related to the isotype of the anti-CD3 Ab used, as was recently suggested by others (56), based on a limited study of a few Abs tested over a limited concentration range (direct comparisons between human and chimpanzee lymphocytes were only performed with two isotypes, and concentrations used started at 300 ng/ml) (56). Rather, any differences observed are specific to individual anti-CD3 clones.…”

Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

“…Siglec-5 manipulation switched the species-type response to T-cell receptor (TCR) stimulation. This species difference may be a factor in Tcell-mediated diseases, including the much milder chimpanzee disease from HIV-1 and hepatitis B or C (94), and the apparent lack of spontaneous rheumatoid arthritis and bronchial asthma. These differences in immunoreactivity could involve the weaker expression of CD33rSiglecs of humans, relative to great apes (93).…”

Effective activation alleviates the replication block of CCR5-tropic HIV-1 in chimpanzee CD4+ lymphocytes

“…We first evaluated a stimulation protocol using anti-CD3 or a combination of anti-CD3 + anti-CD28 monoclonal antibodies (mAbs) and the results were recently reported (Bibollet-Ruche et al, 2008). We found that not all anti-CD3 mAb isotype were equally capable of stimulating chimpanzee T cells.…”