Bystander sensitization to activation-induced cell death as a mechanism of virus-induced immune suppression.
Viral infections which induce strong T-cell responses are often characterized by a period of transient immunodeficiency associated with the failure of host T cells to proliferate in response to mitogens or to mount memory recall responses to other antigens. During acute infections, most of the activated, proliferating virus-specific T cells are sensitized to undergo apoptosis on strong T-cell receptor (TCR) stimulation, but it has not been known why memory T cells not specific for the virus fail to proliferate on exposure to their cognate antigen. Using a lymphocytic choriomeningitis virus (LCMV) infection model in which LCMV-immune Thy 1.1(+) splenocytes are adoptively transferred into Thy 1.2(+) LCMV carrier mice, we demonstrate here that T cells clearly defined as not specific for the virus are sensitized to undergo activation-induced cell death on TCR stimulation in vitro. This bystander sensitization was in part dependent on the expression of Fas ligand (FasL) on the activated virus-specific cells and gamma interferon (IFN-gamma) receptor expression on the bystander T cells. We propose that FasL from highly activated antiviral T cells may sensitize IFN-gamma-conditioned T cells not specific for the virus to undergo apoptosis rather than to proliferate on encountering antigen. This may in part explain the failure of memory T cells to respond to recall antigens during acute and persistent viral infections.
Zarozinski
C C
CC
Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA.
McNally
J M
JM
Lohman
B L
BL
Daniels
K A
KA
Welsh
R M
RM
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002353:Carrier State; D053222:Fas Ligand Protein; D005260:Female; D007108:Immune Tolerance; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000502:physiology; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma