CTLA4 (CD152) modulates the Th subset response and alters the course of experimental Leishmania major infection

Since both the nature and the amplitude of an antigen-specific T cell respo nse are dependent on co-stimulatory signals, we have invesigated the role o f CD28/CD152-mediated T cell co-stimutation in the regulation of experiment al cutaneous leishmaniasis. CD28-deficient mice and their wild-type litterm ates are equally susceptible to Leishmania major infection. Whole anti-CD15 2 antibody significantly exacerbates the disease while anti-CD152 Fab ameli orates the disease in genetically susceptible BALB/c mice but not in C57BL/ 6, a resistant strain. The anti-CD152-induced exacerbation of the disease i s accompanied by increased lL-4-secreting cell number, diminished parasite- specific delayed-type hypersensitivity (DTH) response and augmented anti-2, 4,6-trinitrophenyl (TNP) IgG1 in response to TNP-leishmanial antigen crude soluble antigen (CSA), suggesting an exaggerated Th2 type of response. Anti -CD152 Fab-mediated amelioration of the disease is associated with increase d IFN-gamma-secreting cell number, increased parasite-specific DTH response and enhanced IgG2a isotype in response to TNP-CSA suggesting a Th1 type of response. Unlike TNP-CSA, TNP-keyhole limpet hemocyanin does not induce th e change in Ig isotype, indicating that the immunomodulatory effect of anti -CD152 is antigen specific. Anti-CD152 antibody-induced early change in Th subsets suggests an important role for CD152 in determining the course of L . major infection, perhaps by alteration of Tn subset differentiation.