Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis

Abstract

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy.

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

“…In murine S. mansoni infection, Arg1-expressing macrophages restrain Th2 cytokinedriven inflammation and fibrosis (30,60). Notably, during Leishmania infection in mice, Arg1 contributes to the failure to heal persistent lesions, which is a consequence of impaired T-cell responses to L. major resulting from local depletion of L-arginine by arginase (32). Taken together, these observations indicate that the control of T-cell responses by Arg1 is a common mechanism of immunosuppression in different chronic infectious diseases.…”

“…regulatory mechanism to restrain excessive T-cell responses in schistosomiasis granulomas, in which a Th2 response predominates and NOS2 expression is minimal (30). Moreover, depletion of L-arginine by Arg1 during Leishmania infection impairs Th1 responses required for parasite killing and subsequent lesion healing (31,32). Second, products of L-arginine metabolism by Arg1 can affect parasite fitness directly.…”

Alternatively activated dendritic cells regulate CD4+T-cell polarization in vitro and in vivo

“…Arginase-1 competes with iNOS for L-arginine (6), and one consequence of increased Arginase-1 activity is L-arginine depletion from the local environment. In murine Leishmania major infection, increased arginase activity in parasite-infected MΦs depletes the skin of L-arginine, impairing proliferation of T cells in the lesion (31). Furthermore, MΦ-derived Arginase-1 is required to suppress T-cell proliferation during Th2 infection, where it limits pathology (8).…”

Myeloid‐derived suppressor cells in parasitic infections

“…Interestingly, high arginase activity by monocytes/macrophages and possibly MDSC suppresses both Th1-induced inflammatory pathogenicity during acute schistosomiasis [71] and Th2-induced chronic pathogenicity by suppressing Th2-cell expansion and reducing liver fibrosis [72], extending the lifespan of these animals. On the contrary, arginase-induced L-arginine depletion in L. major lesions leads to local suppression of the protective Th1 response and a nonhealing phenotype [73]. Overall, it is clear that different types of MDSC can be induced during different parasitic infections and that these cells might influence the course of pathogenicity using mechanisms very similar to what is seen for cancer-induced MDSC.…”