CD4 T 细胞计数低的人群中，致病性隐球菌引起的全球感染负担相当大。此前，我们从新型隐球菌中删除了三个几丁质脱乙酰酶基因，以创建一种缺乏壳聚糖的无毒菌株，命名为 cda1Δ2Δ3Δ，当用作疫苗时，可以保护小鼠免受强毒新型隐球菌菌株 KN99 的攻击。在这里，我们探讨了保护的免疫学基础。在缺乏 B 细胞或 CD8 T 细胞的小鼠中，疫苗介导的保护得以维持。相比之下，缺乏 α/β T 细胞或 CD4 T 细胞的小鼠则失去了保护作用。此外，来自接种疫苗的小鼠的 CD4 T 细胞在过继转移给幼鼠时提供了保护。重要的是，虽然在疫苗接种前单克隆抗体介导的 CD4 T 细胞耗竭导致保护作用完全丧失，但在疫苗接种后但攻击前耗竭 CD4 T 细胞的小鼠中仍保留了显着的保护作用。在干扰素-γ (IFNγ)、肿瘤坏死因子 α (TNFα) 或白细胞介素 (IL)-23p19 遗传缺陷的小鼠中，疫苗介导的保护作用消失。在接种疫苗和受到攻击的小鼠的肺部中发现白细胞以及表达 IFNγ 和 TNFα 的 CD4 T 细胞大量涌入。最后，离体刺激的肺细胞产生较高水平的 IFNγ 与肺部真菌负荷较低相关。因此，虽然 B 细胞和 CD8 T 细胞是可有可无的，但 IFNγ 和 CD4 T 细胞在 cda1Δ2Δ3Δ 疫苗接种之前产生保护性免疫方面具有重叠的作用。然而，一旦接种疫苗，保护作用就不再依赖于 CD4 T 细胞，这表明在 CD4 T 细胞丧失之前为 HIV 感染者接种疫苗的策略。新型隐球菌每年导致超过 100,000 人死亡，其中大多数是 CD4 T 细胞受损的人功能如艾滋病。目前还没有批准的人类疫苗。我们之前创建了一种基因工程的新型隐球菌无毒菌株，命名为 cda1Δ2Δ3Δ。当用作疫苗时，cda1Δ2Δ3Δ可以保护小鼠免受有毒力的新型隐球菌菌株的后续攻击。在这里，我们定义了负责疫苗介导保护的免疫系统组成部分。我们发现，虽然 B 细胞和 CD8 T 细胞是可有可无的，但基因缺陷 CD4 T 细胞和细胞因子 IFNγ、TNFα 或 IL-23 的小鼠却失去了保护作用。感染后，在接种疫苗的小鼠肺部发现大量产生细胞因子的 CD4 T 细胞大量涌入。重要的是，疫苗接种后 CD4 T 细胞耗尽的小鼠仍保留了保护作用，这表明有一种策略可以保护未来面临 CD4 T 细胞功能障碍风险的人。

The global burden of infections due to the pathogenic fungus Cryptococcus is substantial in persons with low CD4+ T-cell counts. Previously, we deleted three chitin deacetylase genes from Cryptococcus neoformans to create a chitosan-deficient, avirulent strain, designated as cda1∆2∆3∆, which, when used as a vaccine, protected mice from challenge with virulent C. neoformans strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8+ T cells. In contrast, protection was lost in mice lacking α/β T cells or CD4+ T cells. Moreover, CD4+ T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4+ T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4+ T cells after vaccination but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in interferon-γ (IFNγ), tumor necrosis factor alpha (TNFα), or interleukin (IL)-23p19. A robust influx of leukocytes and IFNγ- and TNFα-expressing CD4+ T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNγ production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8+ T cells are dispensable, IFNγ and CD4+ T cells have overlapping roles in generating protective immunity prior to cda1∆2∆3∆ vaccination. However, once vaccinated, protection becomes less dependent on CD4+ T cells, suggesting a strategy for vaccinating HIV+ persons prior to loss of CD4+ T cells.The fungus Cryptococcus neoformans is responsible for >100,000 deaths annually, mostly in persons with impaired CD4+ T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of C. neoformans, designated as cda1∆2∆3∆. When used as a vaccine, cda1∆2∆3∆ protects mice against a subsequent challenge with a virulent C. neoformans strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8+ T cells were dispensible, protection was lost in mice genetically deficient in CD4+ T cells and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4+ T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4+ T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4+ T-cell dysfunction.