Sugar polymers exacerbate lung GVHD

In this issue of Blood, Uryu et al demonstrate that recognition of a fungal cell wall component, α-mannan (Mn), an Mn (sugar) polymer, by the C-type lectin receptor Dectin-2 on host macrophages leads to a lung chemokine environment conducive to donor T helper (Th)17 accumulation resulting in severe pulmonary graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). These findings shed new light on a long-standing gap in our understanding of the mechanistic link between infections, specifically fungal, and GVHD severity following allo-HSCT.¹ 

Recipients of allo-HSCT are severely immunocompromised due to the administration of immunosuppressive medications given as prophylaxis for GVHD. This leaves the allo-HSCT recipient susceptible to pathogens that would otherwise fail to induce infection in an individual with a healthy immune system. To that end, superficial and systemic mycoses are a serious and often fatal complication of allo-HSCT.²  Clinical observations have suggested that antifungal prophylaxis with fluconazole reduces acute GVHD.³  But the direct mechanistic link between fungal infection and GVHD severity has heretofore never been demonstrated.

Fungal infections are characterized by increased interleukin (IL)-6, which is a critical driver of Th17 differentiation within the lung. Recent studies^4,5  demonstrated that IL-6^−/− allo-HSCT recipients or IL-6 blockade reduced GVHD and decreased total numbers of Th17 cells in the lung with a concomitant decrease in the Th17-associated cytokine IL-17A. However, the mechanism through which IL-6 is induced following allo-HSCT is poorly understood. Notably, previous reports have thus far fallen short of specifically examining how innate immune cells, such as macrophages, are activated to release IL-6 in the context of allo-HSCT. This study by Uryu et al¹  elegantly endeavors to understand this phenomenon and provide insights into how a potentially protective immune response against fungal infection can cause an exacerbation in pulmonary GVHD.

Dectins are C-type lectin receptors that recognize polysaccharide chains composed of multiple carbohydrates on fungal cell walls, mainly α-Mn and β-glucan. α-Mn is recognized by Dectin-2, which is known to activate macrophages, resulting in their production of inflammatory cytokines driving a Th17 skewed response. Furthermore, previous studies have shown that α-Mn ligation of Dectin-2 receptor and the associated Th17 response are essential for candida elimination in mice.⁶  The current study takes the next step to evaluate whether α-Mn, as well as heat-killed Candida albicans, contributes to the severity of acute GVHD following allo-HSCT. Through the injection of α-Mn following allo-HSCT, Uryu et al show that the survival rate of allo-HSCT recipients is significantly decreased. Furthermore, survival is rescued when the same experiments are performed using Dectin-2^−/− recipients. Importantly, allo-transplant of Dectin-2^−/− donor cells into wild-type (WT) recipients with injection of α-Mn results in similar survival to WT donor transplant, suggesting that Dectin-2 signaling is only critical in host cells for exacerbation of GVHD. Fungal infections of the lung are known to significantly contribute to morbidity and mortality following allo-HSCT.²  To that end, the authors demonstrate increased histopathology scores and decreased hemoglobin O₂ saturation of the lungs in allo-HSCT recipients of α-Mn or C. albicans with a corresponding accretion of Th17 cells. The authors clearly show that α-Mn stimulation of isolated macrophages cultured in the presence of CD4⁺ CD25⁻ T cells significantly increases the level of IL-6, IL-17A, and tumor necrosis factor-α with a corresponding increase in de novo Th17 cells, a result that is lost upon use of Dectin-2^−/− macrophages in vitro. Similar examinations following allo-HSCT confirm these results in vivo and highlight a sequential upregulation of cytokines in the lung, consistent with early phase Th17 differentiation (increased IL-6 and IL-1β cytokines) and late-phase Th17-induced pathology (increased IL-23 cytokine). The expression of IL-17A is not sufficient to define the pathogenic activity of Th17 cells.⁷  The authors thus use IL-17–YFP fate mapping mice to further characterize the accumulated IL-17–producing cells in the lung and describe the expression of CCR6 and CCR4, markers previously reported to be expressed on the surface of inflammatory Th17 cells. Furthermore, lung injury induced by α-Mn–accumulated Th17 cells was completely abrogated when purified IL-17^−/− T cells were transferred to recipients.

Like all elegant studies, this study provides new insights while raising further questions. First, this report provides mechanistic insights to previous clinical reports that have noted the high occurrence of pulmonary complications such as idiopathic pneumonia syndrome (IPS), bronchiolitis obliterans, and other noninfectious pulmonary complications associated with GVHD in patients with fungal infections following allo-HSCT.^2,8  It demonstrates a novel and critical role for detection of sugar polymers (α-Mn) in the fungal cell walls by Dectin-2 on host macrophages in driving a Th17 response that leads to worsening of lung GVHD. The study did not address whether similar mechanisms are involved in other fungal (such as Aspergillus) infection–associated aggravation of lung GVHD. Future studies will need to determine whether this process is primarily dependent only on IL-6, which is being increasingly appreciated as the critical mediator of IPS and acute lung GVHD.⁵  The key molecular and cellular interactions, specifically the role of the inflammasome machinery in the macrophages and whether neutrophils or innate lymphoid cells (all shown to be important against fungal infections) are involved, remain to be elucidated.

However, the current study’s novel finding, that macrophage recognition of α-Mn by the Dectin-2 receptor skews alloreactive T cells to inflammatory Th17 cells in the lung, provides new insights into the biology of lung GVHD that could set the groundwork for future mechanistic studies while uncovering new pathways and targets that might facilitate prophylactic and/or therapeutic interventions.