Inherited human CARD9 deficiency impairs lymphoid cell, but not fibroblast, IL-17-mediated immunity

Area of Science:

• Immunology
• Genetics

Background:

• Cardbohydrate Kinase 9 (CARD9) is crucial for innate immunity against fungi, primarily in myeloid cells.
• The role of CARD9 in adaptive immunity, particularly T cell responses, remains less understood.
• Genetic variants in CARD9 are linked to invasive fungal infections.

Purpose of the Study:

• To investigate the functional consequences of a CARD9 variant in a patient with invasive Candida disease.
• To elucidate the mechanisms underlying CARD9 deficiency in both innate and adaptive immune cells.
• To determine the impact of CARD9 deficiency on T cell intrinsic immunity and specific immune responses.

Main Methods:

• Analyzed peripheral blood mononuclear cells (PBMCs) from a patient (P1) with a homozygous CARD9 nonsense variant.
• Assessed cytokine production in response to fungal ligands.
• Quantified frequencies of circulating CD4+ T cell subsets (TH17-like).
• Evaluated in vitro differentiation of naive CD4+ T cells.
• Determined proportions of Candida-specific CD4+ T cells.

Main Results:

• Patient P1 exhibited reduced cytokine production and diminished frequencies of circulating memory CD4+ TH17-like cells.
• In vitro differentiation of naive CD4+ T cells into IL-17-secreting cells was significantly impaired.
• Candida-specific CD4+ T cell responses were selectively reduced in P1.
• The CARD9 variant affected both myeloid cell-mediated innate immunity and CD4+ T cell-intrinsic IL-17-dependent immunity.

Conclusions:

• The identified CARD9 variant is pathogenic, leading to impaired innate and adaptive immune responses.
• CARD9 deficiency impacts CD4+ T cell function, including IL-17 production and antifungal T cell memory.
• This study highlights the dual role of CARD9 in myeloid and T cell immunity against fungal pathogens like Candida.