Inborn errors of human transcription factors governing IFN-γ antimycobacterial immunity.

Inborn errors of immunity (IEI) delineate redundant and essential defense mechanisms in humans. We review 15 autosomal-dominant (AD) or -recessive (AR) IEI involving 11 transcription factors (TFs) and impairing interferon-gamma (IFN-γ) immunity, conferring a predisposition to mycobacterial diseases. We consider three mechanism-based categories: 1) IEI mainly affecting myeloid compartment development (AD GATA2 and AR and AD IRF8 deficiencies), 2) IEI mainly affecting lymphoid compartment development (AR FOXN1, AR PAX1, AR RORγ/RORγT, AR T-bet, AR c-Rel, AD STAT3 gain-of-function (GOF), and loss-of-function (LOF) deficiencies), and 3) IEI mainly affecting myeloid and/or lymphoid function (AR and AD STAT1 LOF, AD STAT1 GOF, AR IRF1, and AD NFKB1 deficiencies). We discuss the contribution of the discovery and study of inborn errors of TFs essential for host defense against mycobacteria to molecular and cellular analyses of human IFN-γ immunity. [Display omitted] • Distinct stages of antimycobacterial IFN-γ immunity revealed by studies of IEI of TFs. • Interleukin (IL)-12 and IL-23, produced by myeloid cells, enhance IFN-γ production. • IFN-γ, produced by lymphocytes, enhances mycobacterial killing in phagocytes. [ABSTRACT FROM AUTHOR]