Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells

Abstract

In response to infection, naïve CD4⁺ T cells differentiate into two subpopulations: T follicular helper (T_FH) cells, which support B cell antibody production, and non-T_FH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4⁺ T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become T_FH cells, delivered IL-2 to nonproducers destined to become non-T_FH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.