TFRC Germline Variants and Inborn Error of Immunity: Mechanistic Insights into Iron-Immune Crosstalk.

Mutations in TFRC, which encodes transferrin receptor 1 (TfR1/CD71), have emerged as a rare but significant cause of inborn error of immunity (IEI). TfR1 is a crucial membrane glycoprotein responsible for receptor-mediated iron uptake, playing fundamental roles in erythropoiesis and immune function, and linking impaired iron homeostasis to profound immune dysfunction. Notably, TFRC deficiency provides a biologically instructive human model demonstrating that iron uptake via TfR1 is a non-redundant metabolic and signaling checkpoint required for antigen receptor–driven immune activation, clonal expansion, and immune homeostasis. This review summarizes the molecular mechanisms of TfR1, including its interactions with transferrin, and explores how pathogenic TFRC mutations impair iron uptake, affect immune cells, lymphocyte activation, and clonal diversity. We also examine TfR1 in the context of immunodeficiency, linking its roles in iron metabolism and immune regulation to clinical outcomes. By integrating current knowledge on TfR1 biology, molecular mechanisms with patients’ clinical presentation, observations, variants, and therapeutic approaches, this review highlights knowledge gaps and unresolved questions, providing a framework for future research toward elucidating TfR1 mechanisms, improving patient diagnosis, and ultimately enabling the development of targeted therapies for TfR1-mediated immunodeficiency.