Loss of Siglec expression on T lymphocytes during human evolution

Abstract

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 ͉ HIV͞AIDS ͉ T cells

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

“…In contrast, other viral infections (i.e., HPV) do not progress to overt disease when there is a predominant inhibitory interaction between NK and target cells (58). Along this line, our finding of low or absent NKp30 expression in AIDSresistant chimpanzees may, at least in part, correspond to mechanisms observed for HPV-associated disease progression and could additionally integrate and complement the recently described relevant expression of ITIM-linked inhibitory CD33-related sialic acid binding Ig-like lectins (Siglecs) on chimpanzee leukocytes, leading to the dampening and control of adaptive immune responses (60). Reduced NK-mediated inflammation, bystander killing, and particularly the dampening of the reciprocal interaction-activation with DCs could result in the specific but not vehement adaptive immune responses that accompany HIV-1 control in this species.…”

Differences in the constitutive and SIV infection induced expression of Siglecs by hematopoietic cells from non-human primates

“…Thus, as described above, humans appeared to have lost the expression of Siglec-5 on T cells [6] as compared with chimpanzees that readily express Siglec-5 on lymphoid cells which was shown to account for their decreased levels of proliferation following TCR ligation. However, as noted herein, Siglec-5 is readily expressed by human monocytes but not by lymphoid or monocytoid cells from RM and SM.…”

“…Firstly, there was a report that the expression of Siglec-5 by lymphoid cells including CD4 + T cells from chimpanzees but not humans was associated with a relative decreased potential for proliferation following activation via the TCR [6] and this decreased proliferative capacity was speculated to contribute to the relative disease resistance of chimpanzees infected with HIV-1 as compared to humans. These observations provided an evolutionary basis for species differences in susceptibility to HIV-1 pathogenesis and since our lab has been studying the simian immunodeficiency virus (SIV) infections of non-human primates, this finding piqued our interest.…”

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…AAV capsid processing and display of peptides on MHC-I molecules might be different in mouse and human hepatocytes or human T cells might be more sensitive to T-cell receptor stimulation. 94 Alternatively, the generation, number, priming or homing of memory T cells might be different in humans compared to animals. A clinical study of AAV2-F.IX co-administered with transient immunosuppression to block the T-cell response to capsid will show if the AAV capsid-directed T-cell response could be blocked.…”