Continuous antigenic stimulation of DO11.10 TCR transgenic mice in the presence or absence of IL-1: possible implications for mechanisms of T cell depletion in HIV disease

Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Hazenberg, Mette D., Fitch, Mark, Emson, Claire, McEvoy-Hein Asgarian, Bridget K., Mold, Jeff E., Miller, Corey, Busch, Robert, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Hellerstein, Mark K. and McCune, Joseph M. 2015. Continuous antigenic stimulation of DO11.10 TCR transgenic mice in the presence or absence of IL-1: possible implications for mechanisms of T cell depletion in HIV disease. Journal of Immunology 195 (9) , pp. 4096-4105. 10.4049/jimmunol.1500799

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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-2d, 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of Acceptance:	18 August 2015
Last Modified:	31 Oct 2022 10:40
URI:	https://orca.cardiff.ac.uk/id/eprint/85676

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