Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 195, Issue 4, Pages 551-561Publisher
OXFORD UNIV PRESS INC
DOI: 10.1086/510852
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Funding
- NCI NIH HHS [N01-CO-12400] Funding Source: Medline
- NIAID NIH HHS [R56 AI054232, 5R01-AI054232-04, R01-AI48484, R01-AI056997, T32-AI07421, R21-AI060451, R01-AI035522] Funding Source: Medline
- NIDCR NIH HHS [R21-DE15090] Funding Source: Medline
- PHS HHS [5K24-A1056986-04] Funding Source: Medline
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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) beta 1-positive regulatory T (T-reg) 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 TGF beta 1 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 TGF beta 1(+) Treg cells and collagen deposition; (2) TGF beta 1(+) inducible T-reg cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGF beta 1(+) T-reg 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, TGF beta 1(+) T-reg cells, and collagen deposition were low. We thus conclude that the response of TGF beta 1(+) Treg cells to immune activation in early SIV/HIV infection is a double-edged sword: TGF beta 1(+) T-reg 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.
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