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The relationship between the extrinsic environment and the internal transcriptional network is circular. Naive T cells first engage with antigen‐presenting cells to set transcriptional differentiation networks in motion. In turn, this regulates specific chemokine receptors that direct migration into distinct lymph node niches. Movement into these regions brings newly activated T cells into contact with accessory cells and cytokines that reinforce the differentiation programming to specify T cell function. We and others have observed similarities in the transcriptional networks that specify both CD4+ T follicular helper (T FH ) cells and CD8+ central memory stem‐like (T SCM ) cells. Here, we compare and contrast the current knowledge for these shared differentiation programs, compared to their effector counterparts, CD4+ T‐helper 1 (T H1 ) and CD8+ short‐lived effector (T SLEC ) cells. Understanding the interplay between cellular interactions and transcriptional programming is essential to harness T cell differentiation that is fit for purpose; to stimulate potent T cell effector function for the elimination of chronic infection and cancer; or to amplify the formation of humoral immunity and longevity of cellular memory to prevent infectious diseases.

Conversations that count: Cellular interactions that drive T cell fate