T-CELL GENETIC BACKGROUND DETERMINES DEFAULT T-HELPER PHENOTYPE DEVELOPMENT IN-VITRO

A host's ability to resist certain pathogens such as Leishmania major can depend upon the phenotype of T helper (Th) subset that develops. D ifferent murine genetic backgrounds are known to significantly alter t he direction of Th subset development, although the cellular basis of this influence is poorly understood. To examine the basis of this effe ct we used an in vitro alpha/beta-T cell receptor (TCR) transgenic sys tem for analysis of Th phenotype development. To control for TCR usage , we derived the DO11.10 alpha/beta-TCR transgene in several genetic b ackgrounds. Our findings suggest that the effects of genetic backgroun d on Th phenotype development reside within the T cell, and not the an tigen-presenting cell compartment. Transgenic T cells from both the B1 0.D2 and BALB/c backgrounds showed development toward either the Th1 o r Th2 phenotype under the strong directing influence of interleukin (I L) 12 and IL-4, respectively. However, when T cells were activated in vitro under neutral conditions in which exogenous cytokines were not a dded, B10.D2-derived T cells acquired a significantly stronger Th1 phe notype than T cells from the BALB/c background, correspondent with in vivo Th responses to Leishmania in these strains. Importantly, these c ytokine differences resulted in distinct functional properties, becaus e B10.D2- but not BALB/c-derived T cells could induce macrophage produ ction of nitric oxide, an important antimicrobial factor. Thus, the ge netically determined default Th phenotype development observed in vitr o may correspond to in vivo Th subset responses for pathogens such as Leishmania which do not initiate strong Th phenotype-directing signals .