Immune responses of mice with T-cell receptor (TCR)gamma delta+ T cells but lacking TCR alpha beta+ cells because of a disruption in the TCR alpha gene, were analysed against alloantigens, soluble protein antigen, killed Mycobacterium tuberculosis and exogenous superantigen. Rejection of skin allografts mismatched for classical major histocompatibility complex (MHC) plus multiple minor H antigens was virtually abrogated but the presence of mismatched Qa-1 non-classical MHC antigens on donor tissue resulted in a significant proportion of TCR alpha-/- mice rejecting such grafts. In view of the proposed role for gamma delta T cells in mycobacterial responses, and particularly against self- or mycobacterial heat-shock protein HSP 65, we examined these responses in TCR alpha-/- mice. Local responses after immunization were low in lymph nodes and no component of these was directed against mycobacterial HSP 65. However, splenic T cells from mutant mice responded strongly to either purified protein derivative (PPD) or M. tuberculosis. Our findings indicate that TCR alpha-/- mice are selectively compromised: while responses to (undefined) mycobacterial antigens were substantial, responses to some other target antigens such as MHC alloantigens and HSP 65, believed to be preferentially recognized by gamma delta receptors, were poor or absent. However, the fact that the mutant mice more readily rejected allografts that are mismatched for the non-classical MHC antigen Qa-1 in addition to classical MHC and minor-H incompatibility, indicates that in some mice the residual immune response, presumed to be by gamma delta cells, is sufficient to cause skin graft rejection and that recognition of non-classical MHC antigens may play an important part in the response.