CD4(+) T cell-mediated protection against a lethal outcome of systemic infection with vesicular stomatitis virus requires CD40 ligand expression, but not IFN-gamma or IL-4.
To investigate the mechanism(s) whereby T cells protect against a lethal outcome of systemic infection with vesicular stomatitis virus, mice with targeted defects in genes central to T cell function were tested for resistance to i.v. infection with this virus. Our results show that mice lacking the capacity to secrete both IFN-gamma and perforin completely resisted disease. Similar results were obtained using IL-4 knockout mice, indicating that neither cell-mediated nor T(h)2-dependent effector systems were required. In contrast, mice deficient in expression of CD40 ligand were more susceptible than wild-type mice, and residual resistance in these mice was almost completely abrogated by depletion of CD8(+) T cells. In keeping with this, mice lacking both MHC class I and class II expression succumbed to the infection, whereas most class II-deficient mice normally survive. Adoptive transfer experiments using B cell- and T cell-deficient recipients revealed that no protection could be obtained in the absence of B cells, whereas treatment with virus-specific immune (IgG) serum controlled viral spreading to the central nervous system (CNS), but did not necessarily accomplish virus elimination. Taken together, these results underscore that B cells are essential in preventing early infection of the CNS, but T cells are required for long-term survival. CD4(+) T cells are most efficient in this context and the key function is to provide cognate help to B cells. However, if CD4(+) cell function is compromised, CD8(+) T cells become critical and may suffice for survival.
Andersen
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C
Institute of Medical Microbiology, Panum Institute, University of Copenhagen, 3C Blegdamsvej, 2200 Copenhagen, Denmark.
Jensen
T
T
Nansen
A
A
Marker
O
O
Thomsen
A R
AR
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand; D016827:CD8 Antigens / Q000502:physiology; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018353:Rhabdoviridae Infections / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*
D000914:Antibodies, Viral; D016827:CD8 Antigens; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D015847:Interleukin-4; D007371:Interferon-gamma