GM-CSF⁺ Th: a central player in autoimmunity

Autoimmune diseases are driven by a breach of self-tolerance, leading to chronic inflammation and organ damage. While the Th1 and Th17 paradigms have long dominated our understanding of T-cell-mediated pathology, a distinct subset of CD4⁺ T helper cells defined by the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a central and non-redundant pathogenic driver. These GM-CSF-producing Th cells orchestrate autoimmune pathology across a spectrum of diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes, among others. Mechanistically, they act as critical amplifiers of inflammation by activating and recruiting myeloid cells, which in turn mediate tissue destruction. Furthermore, they establish vicious feedback loops, enhancing their own differentiation and promoting the function of other effector T cells. Despite their established importance, significant heterogeneity and plasticity exist in their phenotype and regulatory networks, with context-dependent variations across different diseases and species. This review synthesizes our current understanding of these pivotal cells, critically evaluating their classification, molecular identity, and the signaling pathways governing their differentiation. We further dissect their specific roles in major autoimmune diseases and provide a forward-looking perspective on their immense translational potential, from novel therapeutic strategies targeting the GM-CSF axis to their use as biomarkers for patient stratification and monitoring.