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* Laboratory of Cellular and Molecular Immunology, T-Cell Tolerance and Memory Section, National Institutes of Health, Bethesda, MD 20892; and
Medstar Research Institute, Hyattsville 20873, MD and Department of Microbiology and Immunology, Georgetown University Medical Center, Washington DC 20057
Protection from the parasite Leishmania major is mediated by CD4 T cells. BALB/c mice are susceptible to L. major and show a nonprotective immunodominant CD4 T cell response to Leishmania homolog of activated receptor for c-kinase (LACK) 158–173. Host genes that underlie BALB/c susceptibility to L. major infections are poorly defined. DM, a nonclassical MHC class II molecule, due to its peptide editing properties has been shown to 1) edit the repertoire of peptides displayed by APC, and 2) focus the display of epitopes by APC to the immunodominant ones. We tested the hypothesis that deficiency of DM, by causing presentation of a different array of epitopes by infected APC than that presented by DM-sufficient APC, may change the course of L. major infection in the susceptible BALB/c mice. We show herein that unlike their susceptible wild-type counterparts, BALB/c mice deficient in DM are protected from infections with L. major. Furthermore, DM-deficient mice fail to display the immunodominant LACK 158–173 on infected APC. In its place, infected DM–/– hosts show elicitation of CD4 T cells specific for newer epitopes not presented by wild-type L. major-infected APC. Protection of BALB/c DM–/– mice is dependent on IFN-
. DM is thus a host susceptibility gene in BALB/c mice, and Ag processing in the absence of DM results in elicitation of a protective T cell response against L. major infections. This report suggests a novel mechanism to trigger host resistance against pathogens.
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 Supported in part by Department of Defense (award W81XWH-04-0013; to N.K.N.) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. N. K. Nanda, Laboratory of Cellular and Molecular Immunology, Building 4, National Institutes of Health, Bethesda, MD 20892. E-mail address: navreetn2000{at}yahoo.com
3 Abbreviations used in this paper: LACK, Leishmania homolog of activated receptor for c-kinase; BMDC, bone marrow-derived dendritic cell; CLIP, class II invariant chain peptide; DC, dendritic cell; FP, foot pad; Ii, invariant chain; LN, lymph node; 7AAD, 7-aminoactinomycin D; SLA, soluble Leishmania Ag.
4 The online version of this article contains supplemental material.
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