title: Continuous Antigenic Stimulation of DO11.10 TCR Transgenic Mice in the Presence or Absence of IL-1β: Possible Implications for Mechanisms of T Cell Depletion in HIV Disease.
abstract: Untreated HIV disease is associated with chronic immune activation and CD4(+) T cell depletion. A variety of mechanisms have been invoked to account for CD4(+) T cell depletion in this setting, but the quantitative contributions of these proposed mechanisms over time remain unclear. We turned to the DO11.10 TCR transgenic mouse model, where OVA is recognized in the context of H-2(d), to explore the impact of chronic antigenic stimulation on CD4(+) T cell dynamics. To model dichotomous states of persistent Ag exposure in the presence or absence of proinflammatory stimulation, we administered OVA peptide to these mice on a continuous basis with or without the prototypic proinflammatory cytokine, IL-1β. In both cases, circulating Ag-specific CD4(+) T cells were depleted. However, in the absence of IL-1β, there was limited proliferation and effector/memory conversion of Ag-specific T cells, depletion of peripheral CD4(+) T cells in hematolymphoid organs, and systemic induction of regulatory Foxp3(+)CD4(+) T cells, as often observed in late-stage HIV disease. By contrast, when OVA peptide was administered in the presence of IL-1β, effector/memory phenotype T cells expanded and the typical symptoms of heightened immune activation were observed. Acknowledging the imperfect and incomplete relationship between Ag-stimulated DO11.10 TCR transgenic mice and HIV-infected humans, our data suggest that CD4(+) T cell depletion in the setting of HIV disease may reflect, at least in part, chronic Ag exposure in the absence of proinflammatory signals and/or appropriate APC functions.
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110; mike.mccune@ucsf.edu ladellk@gmail.com.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Department of Immunology, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands;
authors.forename: Mette D
authors.initials: MD
authors.lastname: Hazenberg
authors.affiliation: Department of Nutritional Sciences, University of California, Berkeley, Berkeley, CA 94720;
authors.forename: Mark
authors.initials: M
authors.lastname: Fitch
authors.affiliation: Department of Nutritional Sciences, University of California, Berkeley, Berkeley, CA 94720; KineMed Inc., Emeryville, CA 94608;
authors.forename: Claire
authors.initials: C
authors.lastname: Emson
authors.affiliation: Department of Nutritional Sciences, University of California, Berkeley, Berkeley, CA 94720;
authors.forename: Bridget K
authors.initials: BK
authors.lastname: McEvoy-Hein Asgarian
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Jeff E
authors.initials: JE
authors.lastname: Mold
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Corey
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Life Sciences, Whitelands College, University of Roehampton, London SW15 4JD, United Kingdom;
authors.forename: Robert
authors.initials: R
authors.lastname: Busch
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; and Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Department of Nutritional Sciences, University of California, Berkeley, Berkeley, CA 94720; KineMed Inc., Emeryville, CA 94608;
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110; mike.mccune@ucsf.edu ladellk@gmail.com.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D010047:Ovalbumin