TY - JOUR
T1 - A murine locus controlling th1/th2 development and response to il-12 maps to a cytokine gene cluster on chromosome 11
AU - Gorham, J. D.
AU - Guler, M. L.
AU - Mackey, A. J.
AU - Steen, R. G.
AU - Dietrich, W. F.
AU - Murphy, K. M.
PY - 1996/12/1
Y1 - 1996/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33749117376&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:33749117376
SN - 0892-6638
VL - 10
SP - A1444
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -