T cell receptor engagement with CD28 costimulation is generally required for naive T cell activation, whereas reactivation of memory cells is less dependent on CD28 costimulation. We studied this process in chronic beryllium disease, in which the frequency of antigen-specific CD4⁺ T cells in the lung is large and circulating antigen-specific cells are also detectable. In the lung, a large fraction of CD4⁺ T cells stopped expressing CD28 mRNA and protein, and this change in phenotype correlated with lung inflammation. In the presence of concentrations of CTLA-4Ig that inhibited the CD28-B7 interaction, beryllium-specific CD4⁺ T cells in lung were still able to proliferate and secrete IFN-γ in response to beryllium in culture. This functional independence of CD28 costimulation included lung CD28⁺ effector cells. Although lung CD4⁺CD28^– cells retained the ability to secrete Th1-type cytokines in response to beryllium, they showed less proliferative capacity and were more susceptible to cell death compared with CD28⁺ T cells. In contrast to lung cells, inhibition of the CD28-B7 interaction markedly reduced responses of beryllium-specific T cells in blood. Taken together, these findings suggest transition within memory CD4⁺ T cells from CD28 dependence in central memory cells to functional independence and then loss of CD28 expression in effector cells.