PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis.
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-gamma 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 FcgammaR 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.
Liang
Spencer C
SC
Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Greenwald
Rebecca J
RJ
Latchman
Yvette E
YE
Rosas
Lucia
L
Satoskar
Abhay
A
Freeman
Gordon J
GJ
Sharpe
Arlene H
AH
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007894:Leishmania mexicana / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000172:deficiency / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein