CD4+ T cells in the mouse can be subdivided into two fractions based on the level of expression of the CD45RB determinant. Previous studies have shown that these subsets are functionally distinct. We have further characterized the properties of these subpopulations in vivo by injecting them into C. B-17 scid mice. The animals restored with the CD45RB(high)CD4+ T cell population developed a lethal wasting disease with severe mononuclear cell infiltrates into the colon and elevated levels of IFN-gamma mRNA. In contrast, animals restored with the reciprocal CD45RB(low) subset or with unfractionated CD4+ T cells did not develop the wasting or colitis. Importantly, the co-transfer of the CD45RB(low) population with the CD45RB(high) population prevented the wasting disease and colitis. These data indicate that important regulatory interactions occur between the CD45RB(high) and CD45RB(low)CD4+ T cell subsets and that disruption of this mechanism has fatal consequences.