The discovery of CD4⁺ T cell subset–defining master transcription factors and framing of the Th1/Th2 paradigm ignited the CD4⁺ T cell field. Advances in in vivo experimental systems, however, have revealed that more complex lineage-defining transcriptional networks direct CD4⁺ T cell differentiation in the lymphoid organs and tissues. This review focuses on the layers of fate decisions that inform CD4⁺ T cell differentiation in vivo. Cytokine production by antigen-presenting cells and other innate cells influences the CD4⁺ T cell effector program [e.g., T helper type 1 (Th1), Th2, Th17]. Signals downstream of the T cell receptor influence whether individual clones bearing hallmarks of this effector program become T follicular helper cells, supporting development of B cells expressing specific antibody isotypes, or T effector cells, which activate microbicidal innate cells in tissues. These bifurcated, parallel axes allow CD4⁺ T cells to augment their particular effector program and prevent disease.

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