AbstractCytokines signaling through receptors sharing the common γ chain (γc), including IL‐2, IL‐4, IL‐7, IL‐9, IL‐15 and IL‐21, are critical for the generation and peripheral homeostasis of B, T and NK cells. To identify unique or redundant roles for γc cytokines in naive CD4+ T cells, we compared monoclonal populations of CD4+ T cells from TCR‐Tg mice that were γ, γ, CD127–/– or CD122–/–. We found that γ naive CD4+ T cells failed to accumulate in the peripheral lymphoid organs and the few remaining cells were characterized by small size, decreased expression of MHC class I and enhanced apoptosis. By over‐expressing human Bcl‐2, peripheral naive CD4+ T cells that lack γc could be rescued. Bcl‐2+ γ CD4+ T cells demonstrated enhanced survival characteristics in vivo and in vitro, and could proliferate normally in vitro in response to antigen. Nevertheless, Bcl‐2+ γ CD4+ T cells remained small in size, and this phenotype was not corrected by enforced expression of an activated protein kinase B. We conclude that γc cytokines (primarily but not exclusively IL‐7) provide Bcl‐2‐dependent as well as Bcl‐2‐independent signals to maintain the phenotype and homeostasis of the peripheral naive CD4+ T cell pool.See accompanying commentary: http://dx.doi.org/10.1002/eji.200737721