To characterize rhinovirus (RV)-specific T cells, RV16- and RV49-specific CD4 T cells were cloned from peripheral blood, and cytokine secretion and serotype specificity were defined. Each RV-specific clone secreted high levels of interferon-gamma, and several also produced interleukin-4 and -5. To test serotype specificity, each clone was incubated separately with five different RV serotypes. Although 2 of 31 clones proliferated only in response to the virus used in cloning, the rest had significant proliferation in response to 2-5 different serotypes. Thus, RV-specific T cells can be activated by either serotype-specific or shared viral epitopes, raising the possibility that repeated activation of T cells by shared viral determinants in vivo could induce potent recall T cell responses. It is likely that enhanced T cell responses to shared viral epitopes contribute to antiviral activity, airway inflammation, or both.