Stem-like cells at the center of CD4 T cell differentiation

CD4 T cells orchestrate immune responses through differentiation into specialized helper subsets. Traditionally, CD4 T cell differentiation is described as a linear process in which naïve CD4 T cells commit to distinct effector lineages upon activation. However, growing evidence challenging this paradigm has provoked considerable debate about CD4 T cell plasticity. This review describes the emerging concept of stem-like CD4 T cells and how they update our understanding of the fundamental mechanisms that regulate CD4 T cell differentiation. We discuss how stem-like CD4 T cells play a crucial role as precursor cells to distinct effector subsets and explore their implications in cancer, infections, and autoimmunity. Finally, we address how stem-like CD4 T cells might resolve long-standing questions about CD4 T cell plasticity, and propose alternative differentiation models that incorporate this population in chronic diseases.