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The distinction between classical and nonclassical major histocompatibility complex class I molecules helps explain why HLA-G occupies such a unique position in immunoregulation. While classical HLA class I molecules present peptide antigens to cytotoxic T lymphocytes and thereby trigger immune activation, HLA-G evolved under different selective pressures, functioning primarily as a signaling ligand rather than an antigen-presenting platform. Its expression at the maternal-fetal interface established the template for its tolerogenic function: tissues that must coexist with genetically foreign material achieve this coexistence partly by displaying HLA-G, which engages inhibitory receptors on immune cells and converts potentially destructive encounters into tolerant ones. Tumors and persistent pathogens appear to have co-opted this same logic, inducing or upregulating HLA-G to cloak themselves from immune surveillance. The review’s central hypothesis—that fungi may exploit this pathway—fits within a broader pattern in which diverse pathogens converge on shared immunoregulatory circuits regardless of their taxonomic origins.

The receptor biology underlying HLA-G function deserves closer consideration because it determines which immune cell populations are affected when HLA-G appears in infected tissue. LILRB1 and LILRB2 belong to a family of immunoglobulin-like transcripts characterized by cytoplasmic motifs that, upon ligand binding, recruit phosphatases capable of dampening activating signaling cascades. When these receptors are engaged on natural killer cells, cytotoxicity is suppressed; when engaged on dendritic cells and macrophages, antigen presentation and pro-inflammatory cytokine production are attenuated; and when engaged on T lymphocytes, proliferation and effector function are curtailed. Because these receptors are distributed across both innate and adaptive lineages, a single tolerogenic molecule can exert coordinated suppression across multiple arms of the immune response simultaneously. This breadth of action distinguishes HLA-G from more narrowly targeted evasion mechanisms, such as fungal capsules that resist phagocytosis or enzymes that degrade complement, and explains why its exploitation would be particularly advantageous for pathogens seeking long-term persistence.

The damage-response framework referenced in the review offers a useful lens for interpreting why HLA-G induction during fungal infection could produce divergent clinical outcomes. According to this framework, the same pathogen-mediated immune alteration can be beneficial, neutral, or harmful depending on the host’s baseline immune status. In an immunocompetent individual, moderate HLA-G induction might serve as a homeostatic brake that prevents collateral tissue damage during fungal clearance, allowing the infection to be resolved without excessive inflammation. In a severely immunocompromised host, however, the same HLA-G activity could tip the balance decisively toward pathogen persistence by suppressing the residual antifungal effector mechanisms that remain. This context-dependence has practical implications: therapeutic interventions aimed at blocking HLA-G signaling would need to be calibrated to the patient’s immune status, since removing a compensatory regulatory mechanism in a hyperinflammatory patient could exacerbate tissue injury even as it enhances fungal killing.

The IL-10–HLA-G feedback loop described in the review warrants additional attention because self-amplifying circuits of this kind can establish stable immunosuppressive microenvironments that are difficult to reverse. When IL-10 induces HLA-G expression, and HLA-G in turn promotes further IL-10 production, the resulting positive feedback can lock infected tissue into a tolerogenic state even after the initial inflammatory trigger has subsided. This dynamic has been documented in chronic viral infections, where sustained IL-10 and soluble HLA-G levels correlate with impaired pathogen-specific T-cell responses and difficulty achieving immune reactivation. If a similar dynamic operates during chronic fungal infections—such as those caused by Candida species colonizing mucosal surfaces or by dimorphic fungi establishing latent infection—the feedback loop could contribute to the persistence and recurrence that characterize these conditions. Disrupting this loop at either node, whether through IL-10 neutralization or HLA-G receptor blockade, represents a potential host-directed therapeutic strategy that would enhance endogenous antifungal immunity rather than targeting the fungus directly.

The role of chitin as a fungal-derived trigger for IL-10 production illustrates how specific structural components of the fungal cell wall can actively shape the immunological tone of the host response. Chitin is normally buried beneath outer layers of glucans and mannoproteins, but it becomes exposed during cell wall remodeling, budding, and damage caused by antifungal drugs. Once accessible, chitin engages pattern recognition receptors including the mannose receptor, NOD2, and Toll-like receptors, and this coordinated signaling preferentially drives IL-10 rather than pro-inflammatory cytokines. This is a striking example of fungal structural biology being repurposed for immune evasion: a molecule that serves an essential structural role in the cell wall simultaneously functions as an immunoregulatory trigger when exposed. The clinical implication is that antifungal treatment itself, by damaging cell walls and exposing chitin, might inadvertently enhance the very immunosuppressive pathways that facilitate persistence, suggesting that combination approaches pairing antifungals with immunoregulatory modulation could be more effective than either alone.

Transforming growth factor-β, the second cytokine highlighted in the review, operates through partially overlapping but mechanistically distinct pathways compared with IL-10. While IL-10 primarily suppresses antigen-presenting cell function and Th1 responses, TGF-β exerts broader effects on immune cell differentiation, promoting the generation of regulatory T cells and inhibiting the differentiation of pro-inflammatory Th17 cells that are important for mucosal antifungal defense. The convergence of IL-10 and TGF-β on HLA-G expression creates a scenario in which multiple regulatory cytokines induced during fungal infection could act synergistically to establish a tolerogenic microenvironment. This convergence is significant because it means that blocking any single cytokine pathway may be insufficient to prevent HLA-G induction; instead, combination strategies targeting multiple regulatory axes simultaneously may be required to fully restore protective antifungal immunity.

The concept of host-directed therapy, which the review identifies as a potential application of this research, represents a growing paradigm in infectious disease management. Rather than developing new antifungal compounds that target pathogen-specific molecules—a strategy constrained by the limited number of druggable fungal targets and the toxicity of many existing agents—host-directed approaches modulate the host environment to make it less permissive for pathogen survival. Blocking HLA-G signaling, neutralizing IL-10 or TGF-β, or disrupting the feedback loops that sustain immunosuppression could restore the efficacy of existing antifungal drugs by reactivating the host’s own effector mechanisms. This approach also has the advantage of being applicable across multiple fungal species, since the host pathways being targeted are shared rather than pathogen-specific.

The translational gap between the mechanistic framework proposed in this review and clinical application remains substantial. Direct evidence that HLA-G is upregulated during human fungal infections is currently limited, and the review’s argument is built largely on the convergence of well-established pathways from other infectious and inflammatory contexts. Demonstrating that HLA-G expression is measurably elevated in tissue biopsies or serum samples from patients with invasive candidiasis, aspergillosis, or other fungal diseases would be a critical first step. Subsequent studies would need to establish that this elevation correlates with clinical outcomes such as treatment failure, fungal persistence, or disease severity, and that interventions targeting the HLA-G pathway can improve outcomes in relevant models. The heterogeneity of fungal infections—with different species, anatomical sites, and host immune contexts potentially producing different HLA-G dynamics—means that the relationship will likely need to be characterized individually for each major fungal pathogen rather than assumed to be universal.

The soluble isoforms of HLA-G, particularly HLA-G5, deserve specific consideration in the context of fungal disease because they can circulate systemically and exert immunoregulatory effects at sites distant from their cellular source. If fungal infections induce soluble HLA-G release from monocytes or other cell types, this could contribute to the systemic immunosuppression observed in invasive fungal disease, potentially explaining why disseminated fungal infections are associated with broad defects in cell-mediated immunity that extend beyond the local site of infection. Measuring soluble HLA-G levels in the serum of patients with invasive mycoses could therefore serve both as a biomarker of disease severity and as a mechanistic indicator of the immunoregulatory processes driving pathogenesis.

The genetic variability of the HLA-G locus adds another dimension to this question. The HLA-G gene is polymorphic, and certain alleles are associated with higher or lower expression levels of both membrane-bound and soluble forms. If fungal pathogens do indeed exploit HLA-G-mediated tolerance, individuals carrying high-expressor alleles might be disproportionately susceptible to fungal persistence or chronic infection, while those with low-expressor variants might be relatively protected. Conversely, the same high-expressor alleles might protect against immunopathology in settings where fungal-induced inflammation is excessive. Understanding how HLA-G polymorphisms influence susceptibility to fungal disease could open new avenues for risk stratification and personalized management of patients at high risk for invasive mycoses, such as those undergoing hematopoietic stem cell transplantation or receiving prolonged immunosuppressive therapy.

The comparison between fungal and viral exploitation of HLA-G is instructive because it highlights both the plausibility of the hypothesis and the specific challenges that fungal infections present. Viruses, as intracellular pathogens, can directly manipulate host gene expression through viral proteins that interfere with transcriptional regulation, making it straightforward to envision how they might upregulate HLA-G. Fungi, as predominantly extracellular pathogens, lack this direct access to the host nucleus and must instead rely on indirect mechanisms—such as inducing host cytokines like IL-10 and TGF-β, or releasing cell wall components that trigger regulatory signaling—to create conditions permissive for HLA-G expression. This indirect route is less efficient but potentially more difficult to block, since it involves multiple host pathways rather than a single viral effector. It also means that the timing and magnitude of HLA-G induction during fungal infection would depend on the complex interplay between fungal burden, host cytokine production, and tissue microenvironmental factors, making the relationship more variable and context-dependent than in viral systems.

The broader significance of this hypothesis extends beyond fungal pathogenesis to the general question of how immune checkpoint pathways are co-opted across infectious diseases. If HLA-G serves as a convergent target for diverse pathogens—viruses, parasites, and potentially fungi—this suggests that it represents a fundamental vulnerability in host defense that pathogens have independently discovered through convergent evolution. Understanding the common principles governing this exploitation could inform therapeutic strategies that are broadly applicable across multiple infectious diseases, rather than being specific to a single pathogen. It also raises the possibility that other immune checkpoint molecules beyond HLA-G, such as programmed death ligand 1 or cytotoxic T lymphocyte-associated antigen 4, may similarly be exploited during fungal infection, creating a network of overlapping immunosuppressive mechanisms that collectively enable persistence.

Future research directions emerging from this framework include the systematic measurement of HLA-G expression in clinical specimens from patients with defined fungal infections, the use of in vitro models to test whether fungal stimuli directly or indirectly induce HLA-G in human monocytes and dendritic cells, and the development of animal models in which HLA-G signaling can be experimentally manipulated to determine its causal role in fungal persistence. Each of these approaches addresses a specific gap in the current evidence base, and together they would provide the foundation needed to translate the mechanistic hypothesis into clinically actionable insights. The intersection of fungal immunology and immune checkpoint biology remains largely uncharted territory, and the framework presented here offers a structured starting point for systematic investigation.

Subject of Research: Immunology

Article Title: Do fungal pathogens exploit HLA-G-mediated immune tolerance?

Article References: AlSaleh, A., & Farid, E. (2026). Do fungal pathogens exploit HLA-G-mediated immune tolerance?. Frontiers in Molecular Biosciences, 13, Article 1963030. https://doi.org/10.3389/fmolb.2026.1963030

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1963030

Keywords: HLA-G, fungal infections, immune evasion, IL-10, TGF-beta, host-directed therapy, fungal, pathogens, exploit, HLA-G-mediated, immune, tolerance