CD8+ T Cells Are Required for Primary Immunity in C57BL/6 Mice Following Low-Dose, Intradermal Challenge withLeishmania major

Abstract

Standard murine models of cutaneous leishmaniasis, involving s.c. inoculation of large numbers of Leishmania major promastigotes, have not supported an essential role for CD8+ T cells in the control of primary infection. Recently, a L. major model combining two main features of natural transmission, low parasite dose and inoculation into a dermal site, has been established in resistant C57BL/6 mice. In the present studies, C57BL/6 mice with CD8+ T cell deficiencies, including CD8−/− and CD8-depleted mice, failed to control the growth of L. major following inoculation of 100 metacyclic promastigotes into the ear dermis. The resulting dermal pathology was minor and delayed. Lesion formation in wild-type mice was coincident with the killing of parasites in the inoculation site. Both events were associated with the accumulation of CD8+ T lymphocytes in the skin and with the capacity of CD8+ T cells recovered from draining lymph nodes or infected dermis to release IFN-γ following coculture with infected dendritic cells. Reconstitution of resistance to L. major in RAG−/− mice using T cells from naive donors was optimal when both CD4+ and CD8+ T cells were transferred. Primed CD8+ T lymphocytes obtained from C57BL/6 mice during the acute stage of infection were able to mediate both pathology and immunity when transferred alone. The low dose, intradermal challenge model reveals that CD8+ T cells play an essential role in both pathogenesis of and immunity to primary infection with L. major in the skin.

CXCR3–/– mice mount an efficient Th1 response but fail to control Leishmania major infection

“…8). While CD4 + Th1 cells are involved in the host defense against L. major [1], CD8 + T cells recruited to the site of infection also play a critical role in resolution of primary L. major infection [43,44]. Furthermore, CXCR3 has been shown to facilitate trafficking of CD8 + T cells into the site of inflammation [26,45].…”

“…Cells from the ear lesions of L. major-infected CXCR3 -/-and CXCR3 +/+ mice were isolated as described previously [43]. Briefly, two sheets of ear were separated and incubated with dermal side down on complete RPMI 1640 at 37 C for 6 h. The cells spontaneously migrating out of the dermis were collected and filtered through 70-lm pore size cell strainer for flow cytometric analysis.…”

Control of Leishmania major in the absence of Tyk2 kinase

“…In contrast, antibodymediated depletion of CD8 + T cells transiently increased the severity of footpad lesions in high dose-infected mice [33]. In the low-dose ear infection model both CD8 -/-and anti-CD8-treated mice developed chronic lesions with high parasite burden [34]. Based on these results, the functional blockade of Tyk2 -/-CD8 + T cells observed in our study is likely to contribute to the disease aggravation observed in Tyk2 -/-mice.…”

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

“…However, limited information is available regarding the molecular details as to how DCs respond to the intracellular amastigotes. As professional APCs and potential targets for Leishmania infection, DCs play multiple roles in leishmaniasis: updating/transporting parasites (Moll et al, 1995), initiating innate immunity (Schleicher et al, 2007), priming parasitespecific CD4 + and CD8 + T cells, and maintaining T cell memory/activity (Baldwin et al, 2004;Belkaid et al, 2002;Bertholet et al, 2005;Zaph et al, 2004). Recently, DC-based vaccination for the control of L. major-induced cutaneous leishmaniasis has gained special attention (Ramirez-Pineda et al, 2004;Remer et al, 2007).…”