TY - JOUR
T1 - OX40 costimulation promotes persistence of cytomegalovirus-specific CD8 Tcells
T2 - A CD4-dependent mechanism
AU - Humphreys, Ian R.
AU - Loewendorf, Andrea
AU - De Trez, Carl
AU - Schneider, Kirsten
AU - Benedict, Chris A.
AU - Munks, Michael W.
AU - Ware, Carl F.
AU - Croft, Michael
PY - 2007/8/15
Y1 - 2007/8/15
N2 - The mechanisms that regulate CMV-specific T cell responses in vivo are poorly understood. During murine CMV infection of B6 mice, primary responses in the spleen are dominated by CD8 T cells reactive with antigenic epitopes in M45, M57, and m139 murine CMV gene products. However, during the later persistent phase of infection, CD8 T cell responses to epitopes in m139 and M38 viral gene products predominate. The basis for this shift in CD8 T populations is unknown. In this study, we demonstrate that OX40, a TNFR superfamily member, specifically regulates the accumulation of CD8 T cells reactive with the persistent-phase epitopes. Defective CD8 T cell responses in OX40-/- mice were replicated in MHC class II-/- mice implying that CD4 T cells in part controlled the differentiation of the CD8 T cell clones responsive to these epitopes during persistent infection. Furthermore, treatment of infected mice with an agonist OX40 Ab induced expansion of protective primary virus-specific CD8 T cells independent of CD4 T cell help, but CD4 T cells were crucial for anti-OX40 to promote CD8 T cells reactive to the persistent dominant epitopes. Collectively, these results indicate manipulation of OX40 may be useful in improving cellular immunotherapy regimes for treatment of persistent virus infections.
AB - The mechanisms that regulate CMV-specific T cell responses in vivo are poorly understood. During murine CMV infection of B6 mice, primary responses in the spleen are dominated by CD8 T cells reactive with antigenic epitopes in M45, M57, and m139 murine CMV gene products. However, during the later persistent phase of infection, CD8 T cell responses to epitopes in m139 and M38 viral gene products predominate. The basis for this shift in CD8 T populations is unknown. In this study, we demonstrate that OX40, a TNFR superfamily member, specifically regulates the accumulation of CD8 T cells reactive with the persistent-phase epitopes. Defective CD8 T cell responses in OX40-/- mice were replicated in MHC class II-/- mice implying that CD4 T cells in part controlled the differentiation of the CD8 T cell clones responsive to these epitopes during persistent infection. Furthermore, treatment of infected mice with an agonist OX40 Ab induced expansion of protective primary virus-specific CD8 T cells independent of CD4 T cell help, but CD4 T cells were crucial for anti-OX40 to promote CD8 T cells reactive to the persistent dominant epitopes. Collectively, these results indicate manipulation of OX40 may be useful in improving cellular immunotherapy regimes for treatment of persistent virus infections.
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U2 - 10.4049/jimmunol.179.4.2195
DO - 10.4049/jimmunol.179.4.2195
M3 - Article
C2 - 17675479
AN - SCOPUS:34848849793
SN - 0022-1767
VL - 179
SP - 2195
EP - 2202
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -