CD40-CD40 ligand costimulation is not required for initiation and maintenance of a Th1-type response to Leishmania major infection.
Although previous studies demonstrated a requirement for CD40-CD40 ligand (CD40L) interaction in the development of resistance to Leishmania infection, we recently showed that mice lacking the gene for CD40L (CD40L(-/-) mice) can control Leishmania major infection when they are infected with reduced numbers of parasites. In this study, we examine the cytokine pattern in healing versus nonhealing CD40L(-/-) mice and investigated whether CD40 activation is required for resistance to reinfection. We observed that CD4(+) cells in healed CD40L(-/-) mice produce high levels of gamma interferon compared to cells from nonhealing, high-dose-inoculated mice. In addition, we observed a higher frequency of interleukin-12 (IL-12)- producing cells and a reduced number of IL-4-producing cells in mice infected with reduced numbers of parasites. Importantly, we found that healed CD40L(-/-) mice are highly resistant to reinfection with a large parasite inoculum. In addition, by comparing the cytokine patterns at an early and late stage of infection in nonhealing CD40L(-/-) mice, we demonstrated that nonhealing CD40L(-/-) mice produce a weak Th1-type response during the early stage of infection, but this response wanes as a Th2-type response emerges during late stages of infection. Anti-IL-4 antibody treatment, starting either at the beginning of infection or at week 4 postinfection enabled CD40L(-/-) mice to control a high-dose infection. Together, these results show that CD40-CD40L interaction, although important for IL-12 production in high-dose infections, is not required for either the development or maintenance of resistance in mice infected with reduced numbers of parasites.
Padigel
Udaikumar M
UM
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Farrell
Jay P
JP
D000818:Animals; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000502:physiology; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology*
D019013:CD40 Antigens; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma