Differential Biological Role of CD3 Chains Revealed by Human Immunodeficiencies

Abstract

The biological role in vivo of the homologous CD3γ and δ invariant chains within the human TCR/CD3 complex is a matter of debate, as murine models do not recapitulate human immunodeficiencies. We have characterized, in a Turkish family, two new patients with complete CD3γ deficiency and SCID symptoms and compared them with three CD3γ-deficient individuals belonging to two families from Turkey and Spain. All tested patients shared similar immunological features such as a partial TCR/CD3 expression defect, mild αβ and γδ T lymphocytopenia, poor in vitro proliferative responses to Ags and mitogens at diagnosis, and very low TCR rearrangement excision circles and CD45RA+ αβ T cells. However, intrafamilial and interfamilial clinical variability was observed in patients carrying the same CD3G mutations. Two reached the second or third decade in healthy conditions, whereas the other three showed lethal SCID features with enteropathy early in life. In contrast, all reported human complete CD3δ (or CD3ε) deficiencies are in infants with life-threatening SCID and very severe αβ and γδ T lymphocytopenia. Thus, the peripheral T lymphocyte pool was comparatively well preserved in human CD3γ deficiencies despite poor thymus output or clinical outcome. We propose a CD3δ ≫ CD3γ hierarchy for the relative impact of their absence on the signaling for T cell production in humans.