B eryllium exposure can lead to the development of beryllium-specific CD4⁺ T cells and chronic beryllium disease (CBD), which is characterized by the presence of lung granulomas and a CD4⁺ T cell alveolitis. Studies have documented the presence of proliferating and cytokine-secreting CD4⁺ T cells in blood of CBD patients after beryllium stimulation. However, some patients were noted to have cytokine-secreting CD4⁺ T cells in blood in the absence of beryllium-induced proliferation, and overall, the correlation between the 2 types of responses was poor. We hypothesized that the relative proportion of memory T cell subsets determined antigen-specific proliferation. In most CBD patients, the majority of beryllium-specific CD4⁺ T cells in blood expressed an effector memory T cell maturation phenotype. However, the ability of blood cells to proliferate in the presence of beryllium strongly correlated with the fraction expressing a central memory T cell phenotype. In addition, we found a direct correlation between the percentage of beryllium-specific CD4⁺ T_EM cells in blood and T cell lymphocytosis in the lung. Together, these findings indicate that the functional capability of antigen-specific CD4⁺ T cells is determined by the relative proportion of memory T cell subsets, which may reflect internal organ involvement.