Cell contact-mediated macrophage activation for antileishmanial defence: mapping of the genetic restriction to the I region of the MHC.
Employing a murine model of cutaneous leishmaniasis, we observed that draining popliteal lymph node Lyt-1+2- T cells from C57BL/6 mice with Leishmania major (also called L. tropica major) footpad infections activate macrophages in vitro to kill intracellular Leishmania amastigotes. This antileishmanial effect requires direct contact between T cell effectors and infected macrophage targets. Furthermore, it neither is strictly lymphokine mediated nor causes damage to infected macrophages; and it is antigen specific. Syngeneic combinations of L. major sensitized T cells and target macrophages result in maximum antileishmanial effects whereas allogeneic combinations result in minimum effects. The present study examined the nature of this genetic restriction and specifically investigated whether it was under the control of Major Histocompatibility Complex (MHC) gene products. Using combinations of L. major sensitized T cells and infected macrophages obtained from different inbred and congenic mouse strains in the in vitro antileishmanial assay, we determined that antileishmanial effects occur optimally when the target and effector cells are derived from mice with the same I-A haplotype. These results suggest that I-A encoded gene products play a role in the genetic restriction of contact mediated activation of macrophages for antileishmanial defence. We postulate that an antigen-Ia complex may provide for close physical interactions between effector and target cells and may approximate putative T cell membrane-bound activating molecules (as yet unidentified) with the macrophage plasma membrane. Such an association might result in a more efficient delivery system for macrophage activating factors than is afforded by soluble lymphokine mediators.
D000818:Animals; D002450:Cell Communication; D005260:Female; D005802:Genes, MHC Class II; D006183:H-2 Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007896:Leishmaniasis / Q000235:genetics / Q000276:immunology*; D008222:Lymphokines / Q000276:immunology; D008262:Macrophage Activation; D051379:Mice; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology
D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D008222:Lymphokines