A subset of Lyt2+ cells has been shown to possess helper activity. The activation of these cells is contingent upon the presence of an allo class I difference and serves to activate CTLs directed against the same class I antigen. There are no data that currently support the existence of Lyt2+T helpers responsive to Minor H antigens or TNP lated cells. We have recently noted a striking correlation between the frequency of Lyt2+ T helpers specific for the class I differences defined by the Kb mutant series and the rate of skin graft rejection of these mutants by B6 mice. Specifically, rapid rejection of bml skin (different from B6 by 3 amino acid substitutions in the Kb moiety) by B6 animals is noted whereas bm6 skin (also different from B6 by several amino changes in the Kb region) is either rejected extremely slowly or fails to reject. When precursor frequencies of various subpopulations are examined, a striking discrepancy is noted in the frequency of the Lyt2+ T helper with that directed against bml being 1/36,000 and that directed against bm6 being 1/greater than 2 million. The precursor frequencies of the L3T4+ T helpers and that of the CTLs are of the same order of magnitude. We are therefore attempting to clarify the role of these cells in the rejection of various types of skin grafts, specifically class I, class II, and minor only different grafts. Preliminary results indicate that Lyt2+ cells are responsible for rejection of class I only different grafts whereas L3T4+ cells appear to be necessary for rejection of class II only different grafts.