Siggs Owen M, Miosge Lisa A, Daley Stephen R, Asquith Kelly, Foster Paul S, Liston Adrian, Goodnow Christopher C
Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia;
J Immunol. 2015 Mar 15;194(6):2587-95. doi: 10.4049/jimmunol.1400326. Epub 2015 Feb 6.
Gene variants that disrupt TCR 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 Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76), for example, cause an arrest of T cell positive selection, whereas 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. In this study we describe 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.
破坏TCR信号传导的基因变异可导致严重的免疫缺陷，然而破坏性较小的变异有时与免疫病理相关。例如，编码76 kDa含Src同源2结构域的白细胞蛋白（SLP - 76）的基因发生无效突变会导致T细胞阳性选择停滞，而一个合成的膜靶向等位基因允许有限的阳性选择，但与促炎细胞因子产生和自身抗体相关。这些以及其他神秘结果是由于耐受性信号传导的生化解偶联，还是仅仅是蛋白质活性的定量降低，仍有待确定。在本研究中，我们描述了Lcp2的一种剪接变体，它使野生型SLP - 76蛋白的量减少了约90%，不同程度地破坏了免疫原性和耐受性途径。突变小鼠产生了过量的促炎细胞因子、自身抗体和IgE，表明SLP - 76的简单定量减少足以引发免疫失调。该等位基因揭示了SLP - 76在免疫平衡和免疫失调中的剂量敏感阈值，这是非典型临床免疫缺陷的常见干扰因素。
