title: Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating programmed cell death-1-mediated CD4+ T cell exhaustion.
abstract: The breakdown of L-arginine to ornithine and urea by host arginase supports Leishmania proliferation in macrophages. Studies using arginase-null mutants show that Leishmania-derived arginase plays an important role in disease pathogenesis. We investigated the role of parasite-derived arginase in secondary (memory) anti-Leishmania immunity in the resistant C57BL/6 mice. We found that C57BL/6 mice infected with arginase-deficient (arg(-)) L. major failed to completely resolve their lesion and maintained chronic pathology after 16 wk, a time when the lesion induced by wild-type L. major is completely resolved. This chronic disease was associated with impaired Ag-specific proliferation and IFN-γ production, a concomitant increase in programmed cell death-1 (PD-1) expression on CD4(+) T cells, and failure to induce protection against secondary L. major challenge. Treatment with anti-PD-1 mAb restored T cell proliferation and IFN-γ production in vitro and led to complete resolution of chronic lesion in arg(-) L. major-infected mice. These results show that infection with arg(-) L. major results in chronic disease due in part to PD-1-mediated clonal exhaustion of T cells, suggesting that parasite-derived arginase contributes to the overall quality of the host immune response and subsequent disease outcome in L. major-infected mice. They also indicate that persistent parasites alone do not regulate the quality of secondary anti-Leishmania immunity in mice and that the quality of the primary immune response may be playing a hitherto unrecognized dominant role in this process.
authors: Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors: Zhirong
authors: Z
authors: Mou
authors: Helen M
authors: HM
authors: Muleme
authors: Dong
authors: D
authors: Liu
authors: Ping
authors: P
authors: Jia
authors: Ifeoma B
authors: IB
authors: Okwor
authors: Shiby M
authors: SM
authors: Kuriakose
authors: Stephen M
authors: SM
authors: Beverley
authors: Jude E
authors: JE
authors: Uzonna
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D007156:Immunologic Memory; D018320:Leishmania major / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor; D001119:Arginase