PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis

Abstract

To compare the roles of programmed death 1 ligand 1 (PD-L1) and PD-L2 in regulating immunity to infection, we investigated responses of mice lacking PD-L1 or PD-L2 to infection with Leishmania mexicana. PD-L1-/- and PD-L2-/- mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD-L1-/- mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD-L2-/- mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down-regulation of the Th2 response. Both PD-L1-/- and PD-L2-/- mice produced levels of IFN-γ similar to WT mice. However, the development of IL-4-producing cells was reduced in PD-L1-/- mice, demonstrating a role for PD-L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD-L1-/- mice. Although no alterations in Th1/Th2 skewing were observed in PD-L2-/- mice, PD-L2-/- mice exhibited a marked increase in L. mexicana-specific antibody production. Increased Leishmania-specific IgG production may suppress the healing response through FcγR ligation on macrophages. Taken together, our results demonstrate that PD-L1 and PD-L2 have distinct roles in regulating the immune response to L. mexicana. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.