Parasite-Derived Arginase Influences Secondary Anti-LeishmaniaImmunity 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 weeks, a time when the lesion induced by wild type (WT) L. major is completely resolved. This chronic disease was associated with impaired antigen-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 monoclonal antibody 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.

Blockade of the Programmed Death-1 Pathway Restores Sarcoidosis CD4+ T-Cell Proliferative Capacity

“…This observation of spontaneous cytokine expression, reduced T-cell function, and elevated inhibitory receptor expression has been well described in several inflammatory conditions driven by microbial antigens (31)(32)(33). The lung is a unique environment with constant exposure to foreign antigens.…”

Dysfunctional Adaptive Immunity During Parasitic Infections

“…Cutaneous leishmaniasis in humans has been linked to exhaustion of PD-1+ parasite-specific CD8 T cells, which could be functionally improved in vitro through the addition of toll like receptor 2 (TLR2) agonists [50]. Exhausted CD4 T cells have also been described in the context of experimental Leishmania infection [51]. L. major p arasites lacking arginase, a virulence factor that impedes macrophage activation, are able to establish chronic infection in mice.…”

“…In this scenario, parasite-specific CD4 T cells exhibit impaired proliferation and INF-γ expression, similar to CD8 T cells responding to cutaneous leishmaniasis, chronic toxoplasmosis or chronic viral infection. Importantly, the biological relevance of PD-1 during chronic Leishmania infection was also revealed by in vivo studies in which anti-PD-1 mAb effectively restored parasite-specific CD4 T cell function and resolved chronic infections in rodents [51]. …”

Impairment of T Cell Function in Parasitic Infections

“…Infection of otherwise resistant C57Bl/6 mice with arginase-deficient ( arg −/− ) L. major causes chronic persistence of cutaneous lesions associated with exhaustion of specific CD4 T cells from the draining lymph nodes. The appearance of exhausted CD4 T cells at the chronic phase appears to be a consequence of the reduced primary CD4 response after infection with the transgenic/attenuated parasite [64]. Possibly, the curtailed acute response to arg −/− parasites precludes effective parasite elimination, which subsequently fosters the exhaustion of effector CD4 T cells due to antigen persistence.…”