Although this chapter ought to summarize the role of MHC antigens in T cell activation, the immunobiological meaning of the polymorphism of Class II antigens, as well as that of Class I antigens, is still unresolved. The antigen-presenting ability of human APC is dominant over that of murine APC in the stimulation of antigen-specific xenogeneic T cells. In addition, xenoreactive murine T cells specific for human PBL failed to recognize the polymorphic determinant of Class II antigens of human MHC. On the basis of the data, Class II antigens may be seen to have some role as antigen-presenting molecules rather than as restricting molecules, at least, in the xenogeneic APC-T cell interaction or the xenogeneic MLR responses. These data together with the fact that the linkage disequilibrium found among the various groups of alleles encoding Class I and II antigens making up an MHC haplotypes suggest that the MHC may play a key role during evolution. These studies using xenogeneic cell interaction may shed some light on the immunobiological function of polymorphism of MHC antigens in the mechanisms of T cell activation, and the evolutional history of the polymorphism of the NHC in self or not-self recognition by T cells.