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Despite the public health threat that Staphylococcus aureus (SA) poses, there is no available vaccine. Clinical trials testing vaccine candidates targeting SA surface antigens have had to be ended prematurely due to higher rates of detrimental effects in vaccinated groups when compared to placebo groups. Poststudy analyses of both preclinical and clinical data show that high levels of IFN�� and low levels of IL-17a may be the main drivers of detrimental effects following surface antigen immunization. Here we show that in a mouse bacteremia model, detrimental effects following whole cell vaccination can be lessened depending on the adjuvant used with immunization. We also show that when immunizing with inert mutants of SA superantigens and pore-forming toxins, using certain adjuvants results in a decrease of disease severity by means of producing a stronger antibody response against superantigens as well as greater production of regulatory cytokines (IL-10, TNF��) known to be effective in combating SA.

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Biallelic mutations in NCKAP1L, a regulator of the actin cytoskeleton, cause immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Impaired immune synapse formation, early T cell activation and leading edge formation, and defective neutrophil migration characterize this novel “actinopathy.”, The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.