Lymphotoxin alpha-/- mice develop functionally impaired CD8+ T cell responses and fail to contain virus infection of the central nervous system.
Recent observations have indicated that viral persistence and tumor spreading could occur because of effector function-defective CD8(+) T cells. Although chronic exposure to Ag, lack of CD4 help, and epitope dominance are suggested to interfere with CTL differentiation, mechanisms underlying the defective effector function remain obscure. We demonstrate in this report that lymphotoxin alpha-deficient mice develop CD8(+) T cells at normal frequencies when infected with HSV or immunized with OVA Ag but show impaired cytotoxic and cytokine-mediated effector functions resulting in enhanced susceptibility to HSV-induced encephalitis. Although these cells display near normal levels of perforin and Fas ligand, they remain largely at a naive state as judged by high expression of CD62 ligand and failure to up-regulate activation or memory markers. In particular, these CD8(+) T cells revealed inadequate expression of the IL-12 receptor, thus establishing a link between CTL differentiation and LTalpha possibly through regulation of IL-12 receptor. Viruses and tumors could evade immunity by targeting the same pathway.
Kumaraguru
U
U
Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA.
Davis
I A
IA
Deshpande
S
S
Tevethia
S S
SS
Rouse
B T
BT
D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018792:Encephalitis, Viral / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D008233:Lymphotoxin-alpha; D010047:Ovalbumin