While the precise molecular basis of mouse strain-specific differential response to the pathogen Leishmania major is unknown, development of T helper phenotype (Th1/Th2) plays the critical role in determining resistance. In an in vitro Th1/2 developmental model system, identically cultured CD4+ T cells from susceptible (BALB/c) and resistant (B10.D2) strains develop to Th2and Th1-like phenotypes, respectively. Furthermore, CD4+ T cells from these strains differentially regulate the maintenance of IL-12 responsiveness, with BALB/c losing and B10.D2 maintaining responsiveness, respectively. We have exploited this difference to identify the controlling genetic loci. T cells from all F1 (BALB/c x B10.D2), and 10 of 18 BC1 (F1 x BALB/c) mice maintained IL-12 responsiveness, suggesting a single, dominant locus. Genome-wide SSLP analysis of 72 phenotypically characterized BC1 mice mapped this locus to the middle of chromosome 11 (%2 = 34.7; lod score = 8.2). Interestingly, several genes relevant to T helper cell development are tightly linked to this locus, Including IL-4, -3, -5, and Interferon Regulatory Factor-1 (IRF-1). Allellc variants of one or more of these genes may differentially control response to IL-12, development of Th1/2 phenotype, and, ultimately, disease pathogenesis.
|State||Published - Dec 1 1996|