TCR expression was evaluated in lung transplant patients to determine whether T cells infiltrating rejecting lung allografts employed restricted V beta elements. Serial bronchoalveolar lavage (BAL) specimens were obtained from six lung transplant recipients at approximately 3 wk, 6 wk, and 3 mo post-transplant. T cell lines were established by culturing lavage cells with irradiated donor splenocytes in the presence of low dose IL-2 for 3 wk, and TCR V beta usage was determined by quantitative reverse transcriptase-PCR. Patients were grouped into three categories based on TCR V beta profiles and the clinical status of the allograft. 1) In one patient, BAL-derived T cells expressed heterogeneous V beta repertoires at all time points evaluated. This patient did not experience graft rejection during the 16-mo period of observation, though respiratory infections were diagnosed. 2) In three patients, V beta usage by BAL-derived T cells was restricted during allograft rejection episodes, but was heterogeneous in the absence of rejection and during respiratory infections. In one of these patients, similar V beta repertoires were employed by BAL cells during multiple rejection episodes. 3) In two patients, restricted V beta usage by BAL-derived T cells was observed before and during rejection episodes. Collectively, these data illustrate that human lung allograft rejection, but not pulmonary infection, is associated with T cells expressing a limited number of V beta families. Restricted V beta usage by graft-reactive T cells may allow for the selective elimination of these cells using TCR-specific reagents, thereby promoting allograft-specific tolerance.