Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti–IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti–IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti–IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti–IFN-γ autoantibody–associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.

Anti-interferon (IFN)–γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ–reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10−9 M) binding to IFN-γ, but only eight neutralized IFN-γ–STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I–III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1–IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody–IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ–responsive cells.

Neutralizing anti–interferon-γ (IFN-γ) autoantibodies (nAIGAs) impair IFN-γ–mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, Talaromyces marneffei , and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor–irresponsive IFN-γ variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-γ CAAR T cells lack off-target toxicity, including IFN-γ receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-γ CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-γ CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-γ CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.

Neutralizing autoantibodies (auto-Abs) against type I IFNs (IFN-α and IFN-ω) have emerged as major acquired risk factors for severe viral infections. Human adenovirus (HAdV) is highly prevalent in children and can cause severe pneumonia, but the host determinants of disease severity remain poorly understood. We describe here a 5-year-old child with life-threatening HAdV-B7 pneumonia requiring intensive care who carried high-titer anti–IFN-ω auto-Abs of the IgG1 and IgG3 subclasses. Peripheral blood mononuclear cells produced normal amounts of IFN-α and IFN-ω ex vivo; however, IFN-ω was undetectable in the plasma during acute illness. Functional assays demonstrated that the patient’s plasma strongly neutralized IFN-ω, abolishing its antiviral signaling and protective effects, resulting in high levels of adenovirus replication and virus-induced cytotoxicity. These findings implicate anti–IFN-ω auto-Abs in severe adenoviral infection and support immunological screening of pediatric patients with unexplained severe viral pneumonia, which may guide targeted management.