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J. Exp. Med.,
Volume 187, Number 11, June 1, 1998 1903-1920
By
From the * Institute of Experimental Immunology, Department of Pathology, University Hospital of
Zürich, CH-8091 Zürich, Switzerland; the Aplastic anemia may be associated with persistent viral infections that result from failure of the
immune system to control virus. To evaluate the effects on hematopoiesis exerted by sustained viral replication in the presence of activated T cells, blood values and bone marrow (BM) function were analyzed in chronic infection with lymphocytic choriomeningitis virus (LCMV) in
perforin-deficient (P0/0) mice. These mice exhibit a vigorous T cell response, but are unable to
eliminate the virus. Within 14 d after infection, a progressive pancytopenia developed that
eventually was lethal due to agranulocytosis and thrombocytopenia correlating with an increasing loss of morphologically differentiated, pluripotent, and committed progenitors in the BM.
This hematopoietic disease caused by a noncytopathic chronic virus infection was prevented by
depletion of CD8+, but not of CD4+, T cells and accelerated by increasing the frequency of
LCMV-specific CD8+ T cells in T cell receptor (TCR) transgenic (tg) mice. LCMV and CD8+ T cells were found only transiently in the BM of infected wild-type mice. In contrast,
increased numbers of CD8+ T cells and LCMV persisted at high levels in antigen-presenting cells of
infected P0/0 and P0/0 × TCR tg mice. No cognate interaction between the TCR and hematopoietic progenitors presenting either LCMV-derived or self-antigens on the major histocompatibility
complex was found, but damage to hematopoiesis was due to excessive secretion and action of tumor necrosis factor (TNF)/lymphotoxin (LT)- Division of Hematology, Department of Internal
Medicine, University Hospital of Zürich, CH-8091 Zürich, Switzerland; and the § CNS
Department, Pharmaceutical Research Gene Technologies, F. Hoffmann-La Roche Ltd., CH-4070
Basel, Switzerland
and interferon (IFN)-
produced by CD8+ T
cells. This was studied in double-knockout mice that were genetically deficient in perforin and TNF
receptor type 1. Compared with P0/0 mice, these mice had identical T cell compartments and T cell responses to LCMV, yet they survived LCMV infection and became life-long virus carriers. The
numbers of hematopoietic precursors in the BM were increased compared with P0/0 mice after
LCMV infection, although transient blood disease was still noticed. This residual disease activity was
found to depend on IFN--producing LCMV-specific T cells and the time point of hematopoietic
recovery paralleled disappearance of these virus-specific, IFN--producing CD8+ T cells. Thus, in
the absence of IFN- and/or TNF/LT-, exhaustion of virus-specific T cells was not hampered.
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