Immune responses in newly developed short-lived SAM mice. III. Genetic control of defective helper T-cell activity in in vitro primary antibody response.

Immune activities of newly developed, short-lived SAM-P/1 mice declined sharply after a few months of age. As early as 2 months of age, the activity of T-helper (Th) cells ('Th2'-like) in the in vitro primary antibody response was profoundly impaired, in contrast to normal activity of Th cells ('Th1'-like) engaged in cell-mediated immune responses. Thus, young SAM-P/1 mice show a functional heterogeneity of Th cells. To determine how such a 'Th2' abnormality is inherited in SAM-P/1 mice, immune activities of their hybrids and backcrosses between MHC-identical, high responder B10.BR mice were statistically assessed. The distribution of responses did not support the Mendelian single-gene determination for low responsiveness. Moreover, involvement of a single gene which exhibits incomplete dominance was ruled out because of a continuous distribution pattern of antibody response in the F2 generation. Such an analysis strongly suggests that the impaired 'Th2'-like activity of SAM-P/1 mice is under control of two genes, based on the proportion of low responders in F2 hybrids (29 out of 267, 10.8%) and on calculation according to Wright's formula (n = 1.72). Further linkage analyses suggest that one of the genes is closely linked to albino coat-colour (c) locus on chromosome 7. The putative two genes are likely to control 'differentiation' or 'maturation' of Th2-like cells defectively, but the defect is not refractory, because in vivo-primed Th cells function in vitro as do those in ordinary strains of mice. Possible mechanisms and biological significance in relation to loss of immune activity with ageing are discussed.