A great deal has already been learned from the analysis of beta 2m-mutant mice, but it is clear that a great deal remains to be learned. A significant (though unanticipated) problem with this model system is that it is functionally leaky: residual functional class I expression can be detected in beta 2m- mice, and small numbers of functional CD8+ lymphocytes are present in the animals. In many cases, this has frustrated the initial attempts at obtaining immediate definitive resolution of important questions regarding the function of class I molecules. This has occurred primarily in instances in which the class I-deficient mice fail to express an expected phenotype--for example, in studies showing that beta 2m- mice make adequate protective immune responses against certain intracellular pathogens, and are able to reject some allogeneic tissues with a relatively normal pace. On the other hand, it appears that combining the use of beta 2m- mice with other methods (for example, antibody-mediated depletion of CD8+ T cells) is usually adequate to circumvent these difficulties. It remains to be seen whether other better class I deficiencies can be engineered--for example, large deletions of class I genes or mutations in transcription factors essential for class I gene expression. The extent of immunocompetence of beta 2m- mice was somewhat surprising. It was widely expected that class I-deficient mice would be exquisitely sensitive to many viral infections, though the results indicate that sensitivity varies dramatically with the virus and conditions of infection. However, it appears that in lieu of one major arm of the immune system, compensatory immune mechanisms are in many cases able to deal with infection. Similar conclusions are developing from the analysis of several other recently generated mutant mice. Nevertheless, the results indicate a very important role for class I-directed responses in clearing infections mediated by various viral and parasitic agents, particularly in the case of more severe conditions of infection. Although the class I-deficient mice were initially considered primarily a vehicle for analysis of the role of CD8+ T cells, evidence is accumulating that they manifest deficiencies in several other types of lymphocytes, including NK cells, TCR alpha beta+CD4-CD8- cells, and a subset of TCR gamma delta+ cells. This has been a boon for analysis of the development of these cells, but at the same time it has created difficulties in assigning a biological effect of the mutation to a specific lymphocyte deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)