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Leishmania Antigens Are Presented to CD8⁺ T Cells by a Transporter Associated with Antigen Processing-Independent Pathway In Vitro and In Vivo

Sylvie Bertholet^1,*, Romina Goldszmid^*, Alexandre Morrot^*, Alain Debrabant, Farhat Afrin^2,*, Carmen Collazo-Custodio^3,*, Mathieu Houde, Michel Desjardins, Alan Sher^* and David Sacks^4,*

^* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; and Departement de Pathologie et Biologie Cellulaire, Universite de Montreal, Montreal, Quebec, Canada

CD8⁺ T cells are generated in response to Leishmania major (Lm) or Toxoplasma gondii parasitic infections, indicating that exogenously delivered Ag can be processed for presentation by MHC class I molecules. We show that presentation of Lm nucleotidase (NT)-OVA is TAP independent in vivo and in vitro, and is inhibited by chloroquine, but not by proteasome inhibitors. In contrast, the presentation of T. gondii P30-OVA relies on the TAP/proteasome pathway. Presentation of OVA- or rNT-OVA-coated beads also bypassed TAP requirement above a certain Ag threshold. TAP was also dispensable for the presentation of wild-type Lm Ags to primed CD8⁺ T cells in vitro. Finally, in vivo priming of CD8⁺ T cells involved in acquired resistance to Lm was not compromised in TAP-deficient mice. Thus, Leishmania Ags appear to be confined to an intraphagosomal processing pathway that requires higher concentrations of Ags, suggesting that these parasites may have evolved strategies to impair the efficient endoplasmic reticulum-based, TAP-dependent cross-presentation pathway to avoid or delay CD8⁺ T cell priming.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Infectious Disease Research Institute, Seattle, WA 98104.

² Current address: Center for Biotechnology, Jamia Mamdard, Hamdard University, New Delhi 110062, India.

³ Current address: Food and Drug Administration, Bethesda, MD 20892.

⁴ Address correspondence and reprint requests to Dr. David Sacks, National Institute of Allergy and Infectious Diseases, Laboratory of Parasitic Diseases, Building 4, Room 126, Center Drive MSC 0425, Bethesda, MD 20892-0425. E-mail address: dsacks{at}nih.gov

⁵ Abbreviations used in this paper: ER, endoplasmic reticulum; DC, dendritic cell; DLN, draining lymph node; HFF, human foreskin fibroblast; KO, knockout; Lm, L. major; LN, lymph node; MOI, multiplicity of infection; NT, nucleotidase; Tg, T. gondii; WT, wild type.

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