Extralymphatic virus sanctuaries as a consequence of potent T-cell activation.
T helper cells can support the functions of CD8(+) T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such as the kidneys and other extralymphatic organs. The mechanisms underlying this persistence are not well understood. Here we show that mice with potent virus-specific T-cell responses have reduced levels and delayed formation of neutralizing antibodies, and these mice fail to clear LCMV from extralymphatic epithelia. Transfer of virus-specific B cells but not virus-specific T cells augmented virus clearance from persistent sites. Virus elimination from the kidneys was associated with the formation of IgG deposits in the interstitial space, presumably from kidney-infiltrating B cells. CD8(+) T cells in the kidneys of mice that did not clear virus from this site were activated but showed evidence of exhaustion. Thus, we conclude that in this model of infection, site-specific virus persistence develops as a consequence of potent immune activation coupled with reductions in virus-specific neutralizing antibodies. Our results suggest that sanctuary-site formation depends both on organ anatomy and on the induction of different adaptive immune effector mechanisms. Boosting T-cell responses alone may not reduce virus persistence.
Recher
Mike
M
Institute for Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland. rechermike@bluewin.ch
Lang
Karl S
KS
Navarini
Alexander
A
Hunziker
Lukas
L
Lang
Philipp A
PA
Fink
Katja
K
Freigang
Stefan
S
Georgiev
Panco
P
Hangartner
Lars
L
Zellweger
Raphael
R
Bergthaler
Andreas
A
Hegazy
Ahmed N
AN
Eschli
Bruno
B
Theocharides
Alexandre
A
Jeker
Lukas T
LT
Merkler
Doron
D
Odermatt
Bernhard
B
Hersberger
Martin
M
Hengartner
Hans
H
Zinkernagel
Rolf M
RM
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D007668:Kidney / Q000276:immunology / Q000821:virology; D008099:Liver / Q000276:immunology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000821:virology; D008208:Lymphatic System / Q000276:immunology* / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000254:growth & development / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D017735:Virus Latency / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*