Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor β1-positive regulatory T cells and begins in early infection

Jacob D. Estes, Stephen Wietgrefe, Timothy Schacker, Peter Southern, Greg Beilman, Cavan Reilly, Jeffrey M. Milush, Jeffrey D. Lifson, Donald L. Sodora, John V. Carlis, Ashley T. Haase

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

In human immunodeficiency virus (HIV) infection, collagen deposition and fibrosis within the T cell zone disrupt the lymphatic tissue architecture, contributing to depletion of CD4+ T cells and limiting immune reconstitution. We used relevant animal and in vitro models to investigate the kinetics and possible underlying mechanism(s) of this process. In the lymphatic tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques, we observed parallel increases in immune activation, transforming growth factor (TGF) β1-positive regulatory T (Treg) cells, and collagen type I deposition by 7 days after inoculation, consistent with the hypothesis that early immune activation elicits a countering Treg cell response associated with TGFβ1 expression and collagen deposition. In support of this hypothesis and the possible role of fibrosis in viral pathogenesis, we show (1) spatial colocalization and temporal concordance in levels of TGFβ1+ Treg cells and collagen deposition; (2) TGFβ1+ inducible Treg cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGFβ1+ Treg cells, and collagen deposition in pathogenic SIV infection of macaques, in contrast to apathogenic SIV infection in sooty mangabeys in which levels of immune activation, TGFβ1+ Treg cells, and collagen deposition were low. We thus conclude that the response of TGFβ1 + Treg cells to immune activation in early SIV/HIV infection is a double-edged sword: TGFβ1+ Treg cells normally have a positive effect by limiting immunopathological and autoreactive immune responses, but they also have a negative effect by dampening the antiviral immune response and, as we show here, causing deleterious effects on CD4+ T cell homeostasis by inducing collagen deposition in lymphatic tissues.

Original languageEnglish (US)
Pages (from-to)551-561
Number of pages11
JournalJournal of Infectious Diseases
Volume195
Issue number4
DOIs
StatePublished - Feb 15 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Estes, J. D., Wietgrefe, S., Schacker, T., Southern, P., Beilman, G., Reilly, C., Milush, J. M., Lifson, J. D., Sodora, D. L., Carlis, J. V., & Haase, A. T. (2007). Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor β1-positive regulatory T cells and begins in early infection. Journal of Infectious Diseases, 195(4), 551-561. https://doi.org/10.1086/510852