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© The Rockefeller University Press, 0022-1007/1998/6/1903/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 11, June 1, 1998 1903-1920

Articles

Aplastic Anemia Rescued by Exhaustion of Cytokine-secreting CD8+ T Cells in Persistent Infection with Lymphocytic Choriomeningitis Virus

Daniel Binder*,{ddagger}, Maries F. van den Broek*, David Kägi*, Horst Bluethmann§, Jörg Fehr{ddagger}, Hans Hengartner*, and Rolf M. Zinkernagel*

From the * Institute of Experimental Immunology, Department of Pathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland; the {ddagger} 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

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 x 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)-{alpha} and interferon (IFN)-{gamma} 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-{gamma}–producing LCMV-specific T cells and the time point of hematopoietic recovery paralleled disappearance of these virus-specific, IFN-{gamma}–producing CD8+ T cells. Thus, in the absence of IFN-{gamma} and/or TNF/LT-{alpha}, exhaustion of virus-specific T cells was not hampered.

Key Words: aplastic anemia • lymphocytic choriomeningitis virus • cytotoxic T lymphocytes • cytokines • immune tolerance

Address correspondence to Daniel Binder, Institute of Experimental Immunology, Schmelzbergstr. 12, CH-8091 Zürich, Switzerland. Phone: 41-1-2552989; Fax: 41-1-2554420; E-mail: haembin{at}usz.unizh.ch

Abbreviations used: aa, amino acids; AA, aplastic anemia; BFU-E, burst-forming unit–erythroid; BM, bone marrow; BSS, balanced salt solution; CBC, cellular blood count; CFU-GM, CFU–granulocyte/macrophage; CFU-Meg, CFU–megakaryocyte; CFU-S, CFU–stem cell; gp, glycoprotein; LCMV, lymphocytic choriomeningitis virus; LCMV-GP, glycoprotein of LCMV; LT, lymphotoxin; m, murine; NU, neutralizing units; NSS, normal sheep serum; P0/0, perforin-deficient; p.i., post infection; SPF, specific pathogen-free; tg, transgenic; vacc-LCMV-GP, vaccinia virus recombinant expressing LCMV-GP; wild-type, wt.


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