Tpm1, a locus controlling IL-12 responsiveness, acts by a cell-autonomous mechanism

Th phenotype development is controlled not only by cytokines but also by ot her parameters including genetic background. One site of genetic variation between murine strains that has direct impact on Th development is the expr ession of the IL-12 receptor. T cells from B10.D2 and BALB/c mice show dist inct control of IL-12 receptor expression. When activated by Ag, B10.D2 T c ells express functional IL-12 receptors and maintain IL-12 responsiveness. In contrast, under the same conditions, BALB/c T cells fail to express IL-1 2 receptors and become unresponsive to IL-12, precluding any Th1-inducing e ffects if subsequently exposed to IL-12, Previously, we identified a locus, which we termed T cell phenotype modifier 1 (Tpm1), on murine chromosome 1 1 that controls this differential maintenance of IL-12 responsiveness. In t his study, we have produced a higher resolution map around Tpm1, We produce d and analyzed a series of recombinants from a first-generation backcross t hat significantly narrows the genetic boundaries of Tpm1, This allowed us t o exclude from consideration certain previous candidates for Tpm1, includin g IFN-regulatory factor-1. Also, cellular analysis of F1(B10.D2 x BALB/c) T cells demonstrates that Tpm1 exerts its effect on IL-12 receptor expressio n in a cell-autonomous manner, rather than through influencing the extracel lular milieu. This result strongly implies that despite the proximity of ou r locus to the IL-13/IL-4 gene cluster, these cytokines are not candidates for Tpm1.