Quantitative Reduction of the TCR Adapter Protein SLP-76 Unbalances Immunity and Immune Regulation

Abstract

Gene variants that disrupt T cell receptor signaling can cause severe immune deficiency, yet less disruptive variants are sometimes associated with immune pathology. Null mutations of the gene encoding the scaffold protein SLP-76, for example, cause an arrest of T cell positive selection, while a synthetic membrane-targeted allele allows limited positive selection but is associated with proinflammatory cytokine production and autoantibodies. Whether these and other enigmatic outcomes are due to a biochemical uncoupling of tolerogenic signaling, or simply a quantitative reduction of protein activity, remains to be determined. We describe here a splice variant of Lcp2 that reduced the amount of wild-type SLP-76 protein by ~90%, disrupting immunogenic and tolerogenic pathways to different degrees. Mutant mice produced excessive amounts of proinflammatory cytokines, autoantibodies and IgE, revealing that simple quantitative reductions of SLP-76 were sufficient to trigger immune dysregulation. This allele reveals a dose-sensitive threshold for SLP-76 in the balance of immunity and immune dysregulation: a common disturbance of atypical clinical immune deficiencies.

T Cell Expansion Is the Limiting Factor of Virus Control in Mice with Attenuated TCR Signaling: Implications for Human Immunodeficiency

“…The generation of twp mice and the consequences of the point mutation in Lcp2 for thymocyte maturation and thymic selection are described in Ref. 15. In brief, the mutation leads to a 10-fold reduction in thymic cellularity.…”

“…The twp strain (MGI: 3614800, formal designation Lcp2twp/twp) is described in Ref. 15. Twp mice were backcrossed to P14 mice carrying a transgenic receptor specific for gp33-41 of LCMV (17).…”

“…In this article, we study the antiviral immune response in mice carrying a point mutation in the Lcp2 gene encoding SLP-76 (twp mice). Although mice with a loss-of-function mutation in Lcp2 have no peripheral T cells and a SCID phenotype (12)(13)(14), twp mice have a "hypomorphic" mutation in Lcp2 leading to reduced protein expression and a partial block of thymic development (15). These mice show many features of the human "leaky" SCID phenotype (16) with reduced naive T cells, increased g/d T cells, and clinical signs of immune dysregulation such as antinuclear Abs and elevated IgE (15).…”

Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

“…PKC δ (Prkcd) was significantly up-regulated in WT PA compared to the rest of the group. Also, upregulation of other members of the PKC pathway such as Sele, which promotes adhesion of leucocytes [34], Lcp2 the product of which mediates T-cell receptor mediated signal transduction [52], Nr4a1 the product of which upon translocation from nucleus to mitochondria causes apoptosis [35] was observed. However, PA infection leads to significant downregulation of genes in the PKC pathway including Gna11 encoding the protein belonging to the family of guanine nucleotide-binding proteins (G proteins), which function as modulators or transducers in various transmembrane signaling systems and Prkcz, encoding protein kinase c Z, a member of the PKC family of serine/threonine kinases.…”

Upregulation of <i>GLE</i>1 and <i>LCP</i>2 Genes in H5N1 Influenza Virus Infected Patients

“…Results showed that LCP2 gene was upregulated between two and 40-fold in influenza A virus infected patients at different time points after disease onset, suggesting that upregulation of LCP2 gene may be involved in the activation of intracellular signaling pathways and virus-host interactions. A recent report showed that quantitative reductions of Lcp2 protein in mutant mice produced excessive amounts of proinflammatory cytokines, autoantibodies, and IgE, which revealed a dose-sensitive threshold for Lcp2 protein in the balance of immunity and immune dysregulation [23]. In addition, LCP2 gene was identified as one of the three novel prognostic genes for diffuse large B-cell lymphoma (DLBCL) by using bioinformatic methods [24].…”