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* Department of Biological Sciences, California State University, San Marcos, California 92096;
La Jolla Institute for Allergy and Immunology, San Diego, CA 92109; and
The Scripps Research Institute, La Jolla, CA 92037
Activation of CD4+ T cells helps establish and sustain CD8+ T cell responses and is required for the effective clearance of acute infection. CD4-deficient mice are unable to control persistent infection and CD4+ T cells are usually defective in chronic and persistent infections. We investigated the question of how persistent infection impacted pre-existing lymphocytic choriomeningitis virus (LCMV)-specific CD4+ T cell responses. We identified class II-restricted epitopes from the entire set of open reading frames from LCMV Armstrong in BALB/c mice (H-2d) acutely infected with LCMV Armstrong. Of nine epitopes identified, six were restricted by I-Ad, one by I-Ed and two were dually restricted by both I-Ad and I-Ed molecules. Additional experiments revealed that CD4+ T cell responses specific for these epitopes were not generated following infection with the immunosuppressive clone 13 strain of LCMV. Most importantly, in peptide-immunized mice, established CD4+ T cell responses to these LCMV CD4 epitopes as well as nonviral, OVA-specific responses were actively suppressed following infection with LCMV clone 13 and were undetectable within 12 days after infection, suggesting an active inhibition of established helper responses. To address this dysfunction, we performed transfer experiments using both the Smarta and OT-II systems. OT-II cells were not detected after clone 13 infection, indicating physical deletion, while Smarta cells proliferated but were unable to produce IFN-
, suggesting impairment of the production of this cytokine. Thus, multiple mechanisms may be involved in the impairment of helper responses in the setting of early persistent infection.
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 This work was supported by 5S06GM059833-07 (to B.R.M.), HHSN266200400023C (to A.S. and M.J.B.), AI50840 (to M.J.B.), and National Institutes of Health Grant AI-065359 "Pacific Southwest Center For Biodefense and Emerging Infectious Diseases" (to J.B. and M.J.B.) and LLS 3248-05 (to E.J.). S.C. is a Cancer Research Institute Investigator.
2 Address correspondence and reprint requests to Dr. Bianca R. Mothe, California State University, San Marcos, 333 South Twin Oaks Valley Road, San Marcos, CA 92096. E-mail address: bmothe{at}csusm.edu
3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; PD, programmed death; S, small; L, large; Z, zinc-binding protein; NP, nucleoprotein; GP, glycoprotein precursor; 
-DG, -dystroglycan; ICCS, intracellular cytokine staining; WT, wild type; SFC, spot-forming cell.
This article has been cited by other articles:
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  C. Dow, C. Oseroff, B. Peters, C. Nance-Sotelo, J. Sidney, M. Buchmeier, A. Sette, and B. R. Mothe Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4+ and CD8+ T-Cell Responses J. Virol., December 1, 2008; 82(23): 11734 - 11741. [Abstract] [Full Text] [PDF]
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