Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.
Many chronic viral infections are marked by pathogen persistence and a generalized immunosuppression. The exact mechanisms by which this occurs are still unknown. Using a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate viral targeting of fibroblastic reticular cells (FRC) in the lymphoid organs. The FRC stromal networks are critical for proper lymphoid architecture and function. High numbers of FRC were infected by LCMV clone 13, which causes a chronic infection, whereas few were infected by the acute strain, LCMV Armstrong. The function of the FRC conduit network was altered after clone 13 infection by the action of CD8(+) T cells. Importantly, expression of the inhibitory programmed death ligand 1, which was up-regulated on FRC after infection, reduced early CD8(+) T cell-mediated immunopathology and prevented destruction of the FRC architecture in the spleen. Together, this reveals an important tropism during a persistent viral infection. These data also suggest that the inhibitory PD-1 pathway, which likely evolved to prevent excessive immunopathology, may contribute to viral persistence in FRC during chronic infection.
Mueller
Scott N
SN
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.
Matloubian
Mehrdad
M
Clemens
Daniel M
DM
Sharpe
Arlene H
AH
Freeman
Gordon J
GJ
Gangappa
Shivaprakash
S
Larsen
Christian P
CP
Ahmed
Rafi
R
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002908:Chronic Disease; D005347:Fibroblasts / Q000378:metabolism* / Q000821:virology; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007239:Infections; D008024:Ligands; D008216:Lymphocytic Choriomeningitis / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D013154:Spleen / Q000378:metabolism / Q000821:virology
D007166:Immunosuppressive Agents; D008024:Ligands