Syme R M, Bruno T F, Kozel T R, Mody C H
Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Infect Immun. 1999 Sep;67(9):4620-7. doi: 10.1128/IAI.67.9.4620-4627.1999.
Cell-mediated immunity is critical for the host defense to Cryptococcus neoformans, as demonstrated by numerous animal studies and the prevalence of the infection in AIDS patients. Previous studies have established that the polysaccharide capsule contributes to the virulence of C. neoformans by suppressing T-lymphocyte proliferation, which reflects the clonal expansion of T lymphocytes that is a hallmark of cell-mediated immunity. The present studies were performed to identify the major mechanism by which polysaccharide impairs lymphocyte proliferation, since capsular polysaccharide has the potential to affect the development of T-lymphocyte responses by stimulating production of interleukin-10 (IL-10), inhibiting phagocytosis, and inducing shedding of cell surface receptors. We demonstrate that polysaccharide inhibits lymphocyte proliferation predominantly by blocking uptake of C. neoformans, which is crucial for subsequent lymphocyte proliferation. In addition, we show that polysaccharide did not suppress lymphocyte proliferation via an IL-10-dependent mechanism, nor did it affect critical surface receptor interactions on the T cell or antigen-presenting cell. Having established that polysaccharide impairs phagocytosis, we performed studies to determine whether opsonization with human serum or with anticapsular antibody could reverse this effect. Impaired uptake and lymphocyte proliferation that were induced by polysaccharide can be enhanced through opsonization with monoclonal antibodies or human serum, suggesting that antipolysaccharide antibodies might enhance the host defense by restoring uptake of the organism and subsequent presentation to T lymphocytes. These studies support the therapeutic potential of stimulating cell-mediated immunity to C. neoformans with anticapsular antibody.
细胞介导的免疫对于宿主抵御新型隐球菌至关重要，众多动物研究以及艾滋病患者中该感染的流行情况都证明了这一点。先前的研究已证实，多糖荚膜通过抑制T淋巴细胞增殖来促进新型隐球菌的毒力，这反映了T淋巴细胞的克隆性扩增，而克隆性扩增是细胞介导免疫的一个标志。由于荚膜多糖有可能通过刺激白细胞介素-10（IL-10）的产生、抑制吞噬作用以及诱导细胞表面受体脱落来影响T淋巴细胞反应的发展，因此开展了本研究以确定多糖损害淋巴细胞增殖的主要机制。我们证明，多糖主要通过阻断新型隐球菌的摄取来抑制淋巴细胞增殖，而新型隐球菌的摄取对于随后的淋巴细胞增殖至关重要。此外，我们表明多糖并非通过依赖IL-10的机制抑制淋巴细胞增殖，它也不影响T细胞或抗原呈递细胞上关键的表面受体相互作用。在确定多糖损害吞噬作用后，我们进行了研究以确定用人血清或抗荚膜抗体进行调理是否可以逆转这种效应。通过用单克隆抗体或人血清进行调理，可以增强多糖诱导的摄取受损和淋巴细胞增殖，这表明抗多糖抗体可能通过恢复该生物体的摄取并随后将其呈递给T淋巴细胞来增强宿主防御。这些研究支持了用抗荚膜抗体刺激针对新型隐球菌的细胞介导免疫的治疗潜力。
