The genetic restriction in the T-cell-macrophage-like cell interaction in helper cell induction was investigated with allophenic and irradiation chimeras of various types. Using T cells from P leads to F1 chimeras, there was a restriction of cooperation with the parental haplotype accessory cells, unless the chimeric mice were repopulated with macrophages of the opposite haplotype before priming. T cells from primed or unprimed F1 leads to P chimeras only cooperated with recipient type accessory cells. These observations led to the hypothesis that there are two stages in the genesis of immunocompetence of T helper cells, one dependent on the thymus, and the other on peripheral macrophage-like cells. Purified T cells from P1 + P2 leads to F1 irradiation chimeras behaved in an unexpected manner in the unprimed state, preferring to cooperate with their own haplotype macrophages. This self preference was lost after antigen priming in vivo and was not noted in allophenic chimeras. This loss of self preference was restricted to the haplotypes represented in the chimeras, and did not extend to third party haplotypes. While these in vitro induced helper cells from chimeric mice show clear genetic restrictions at the T-cell macrophage-like cell interaction, there was no evidence for a matching T-B genetic restriction.