Opposing Functions of the T Cell Receptor Kinase ZAP-70 in Immunity and Tolerance Differentially Titrate in Response to Nucleotide Substitutions

Abstract

Null mutations that cripple T cell receptor (TCR) signaling explain rare primary immunodeficiencies, but it is not understood why more common polymorphisms that lead to subtle TCR signaling defects are paradoxically associated with autoimmunity. Here we analyzed how a series of Zap70 variants with step-wise decreases in TCR signaling impacted upon opposing TCR functions of immunity and tolerance. One Zap70 variant, murdock, moderately decreased TCR signaling and thymic selection without compromising immunological tolerance, whereas a more severe Zap70 defect, mrtless, abolished thymic-positive selection and led to immunodeficiency. Signaling capacities between these two thresholds disproportionately compromised negative selection and Foxp3(+) regulatory T cell formation, creating a cellular imbalance between immunogenic and tolerogenic functions that resulted in the excessive production of autoantibodies and immunoglobulin E (IgE). The pleiotropic functions of ZAP-70 and their differential response to graded variation provide a paradigm for understanding the complex outcomes of human genetic variation.

A sharp T-cell antigen receptor signaling threshold for T-cell proliferation

“…All-or-none digital responses on a single-cell level that produce an apparently continuous analog response on a population level are described in the context of other TCR-dependent biological processes, most notably positive selection in the thymus. Titration of signal strength via perturbation of ligand and/or signaling machinery alters the number of positively selecting thymocytes (40,41). Recently, our laboratory has taken advantage of the Nur77-GFP reporter to demonstrate an analogous invariant threshold for positive selection in the thymus (33); titration of Zap70 catalytic activity in fetal thymic organ culture or thymic slice systems alters the number of positively selected thymocytes, but these selected thymocytes nevertheless exhibit an invariant GFP MFI.…”

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

“…The observations in this study suggest that the Cd3z gene could be added to this set of susceptibility genes affecting control of T cell activity. It is known that subtle missense mutations in T cell signaling can lead to dysregulation and autoimmunity (48), and it is likely that the alleles of these genes associated with disease susceptibility are of this type. Identifying and characterizing these genes and biochemical pathways may prove to be important when studying their functional contribution to pathogenesis and for identifying potential therapeutic targets, particularly when overlapping in humans and an animal model of disease.…”

Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

“…mrd/mrd catalytic site mutation, which caused only a 50% decrease in SP cell formation on a polyclonal TCR gene background, nevertheless caused a 50-fold decrease in positive selection of 1G12 + SP thymocytes when introduced into 3A9 TCR transgenic mice (26). We therefore used this sensitive assay to examine whether changes in CD45 isoform expression influenced positive or negative selection.…”