Transgenic Expression of Soluble Human CD5 Enhances Experimentally-Induced Autoimmune and Anti-Tumoral Immune Responses

CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L) of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EμTg), expressing a circulating soluble form of human CD5 (shCD5) as a decoy to impair membrane-bound CD5 function. These shCD5EμTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE), as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma). This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+), and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EμTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens.

分化簇5（CD5）是一种淋巴组织特异性跨膜糖蛋白，可在胸腺细胞、成熟T细胞及B1a淋巴细胞上组成性表达。现有研究数据支持如下观点：CD5是上述细胞中抗原特异性受体介导信号转导的负调控因子，其调控功能或通过与免疫细胞及辅助细胞上表达的、性质尚未明确的CD5配体（CD5L）相互作用实现。为探究体内CD5/CD5L相互作用缺失的功能效应，研究人员构建了新型转基因小鼠品系（shCD5EμTg），该品系可表达人源CD5的循环可溶性形式（shCD5）作为诱饵，以阻断膜结合型CD5的功能。该类shCD5EμTg小鼠对自身抗原的应答显著增强，这一结论可从两方面得到证实：一是其更易出现严重的实验性诱导自身免疫病，包括胶原诱导性关节炎（CIA）与实验性自身免疫性脑脊髓炎（EAE）；二是在非原位癌症模型（B16黑色素瘤）中展现出增强的抗肿瘤应答。这种免疫应答增强的现象，与shCD5EμTg小鼠的检测结果高度吻合：其脾脏与淋巴结中的调节性T细胞（CD4+CD25+FoxP3+）、腹腔内产生IL-10的CD5+B细胞比例显著降低，而脾脏自然杀伤T细胞（NKT）的比例则有所升高。对野生型小鼠反复给予外源性重组shCD5蛋白后，同样可观察到淋巴细胞亚群的上述变化。上述研究数据表明，CD5/CD5L相互作用在部分功能相关淋巴细胞亚群的稳态维持以及自身抗原介导的免疫应答调控中发挥着关键作用。