Fungal infections in CD4 T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8 T cell responses and immunity to inactivated vaccine in the absence of CD4 T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8 T cells in response to inactivated fungal vaccination in a mouse model of CD4 T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8 T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb mice. Augmented CD8 T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORγt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8 T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8 T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients.
In recent years, fungal vaccine research emanated significant findings in the field of antifungal T-cell immunity. The generation of effector T cells is essential to combat many mucosal and systemic fungal infections. The development of antifungal memory T cells is integral for controlling or preventing fungal infections, and understanding the factors, regulators, and modifiers that dictate the generation of such T cells is necessary. Despite the deficiency in the clear understanding of antifungal memory T-cell longevity and attributes, in this review, we will compile some of the existing literature on antifungal T-cell immunity in the context of memory T-cell development against fungal infections.
The global burden of fungal infections is alarming, primarily due to the increasing immune-compromised population. The immuno-preventive/therapeutic measures, including vaccines, are necessary to prevent or control fungal diseases. Identifying a protective host element as a functional phenotypic marker is immensely valuable. We identified a host element, sialophorin, preferentially associated with antifungal memory T cells. We investigated its role in vaccine immunity using a mouse model of pulmonary fungal infection. We found that sialophorin was essential to bolster CD8+ T-cell responses to the vaccine by enhancing their differentiation and expanding cytokine-producing cells required for immunity. Using a gain-of-function approach, activating sialophorin using mAb augmented the CD8+ T cell responses, and sialophorin-sufficient CD8+ T cells were competitively superior in differentiation and expansion to the deficient cells. Sialophorin-mediated vaccine immunity was independent of the T cell trafficking effect. Finally, we show that sialophorin is a potential functional phenotypic marker of fungal vaccine- potency and immunity. Our study revealed that sialophorin is an essential host-target element to bolster vaccine responses and serves as a potential biomarker of fungal immunity.
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