PEDIATRICS Vol. 114 No. 2 August 2004, pp. 552-553
LETHAL T CELL IMMUNODEFICIENCY INDUCED BY CHRONIC COSTIMULATION VIA CD27-CD70 INTERACTIONS
Joseph A. Church, MD
Los Angeles, CA
Tesselaar K, Arens R, van Scijndel GMW, et al. Nat Immunol. 2003;4:49–54
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Purpose of the Study.
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During human immunodeficiency virus (HIV) infection, CD4
+ T
cell levels decline. Studies suggested that this loss is less
likely related to direct infection and killing of these cells
than to exhaustion of the T cell pool induced by chronic immune
activation. The purpose of this study was to determine, in an
animal model, whether artificially induced chronic immune activation
alone could result in clinically significant T cell deficiency.
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Methods.
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Activation of T cells requires stimulation of the antigen-specific
T-cell receptor and ligation of coreceptors on the T cell surface.
One coreceptor on the surface of T cells is CD27, a member of
the tumor necrosis factor receptor family. CD70 is the ligand
for CD27. The investigators generated a CD70-transgenic mouse
model in which CD70 was constitutively expressed on B cells,
resulting in chronic T cell activation in the absence of viral
infection.
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Results.
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These mice demonstrated progressive conversion of naïfive
T cells into effector-memory cells. The end result was depletion
of naïve T cells from lymph nodes and spleen. Despite this
hyperactive immune response, CD70-transgenic mice died as a
result of
Pneumocystis carinii pneumonia, which is an acquired
immunodeficiency syndrome-defining condition among human patients
infected with HIV.
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Conclusions.
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Constant activation of T cells via CD27-CD70 interactions, as
may occur among human subjects during chronic active viral infections,
may result in exhaustion of the T cell pool and the development
of fatal immunodeficiency.
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Reviewer’s Comments.
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It has been unclear how T cell loss occurs during HIV infection.
Some T cells are undoubtedly killed by infection with HIV. However,
the magnitude of the T cell loss is not explained by this pathway.
Very early in the HIV epidemic, it appeared that chronic immune
activation was a hallmark of HIV disease. Was the immune activation
a cause of T cell loss or simply the effect of chronic viral
infection? In other primates, chronic infection with retroviruses
may not cause any detectable immune dysfunction if immune activation
is not induced. This study clearly demonstrated that immune
activation alone might be sufficient to induce T cell deficiency.
If the virus cannot be eradicated, then perhaps induction of
immunologic tolerance to it may be the next best thing.
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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Purpose of the Study.
Methods.
