OX40 costimulation promotes persistence of cytomegalovirus-specific CD8 T Cells: A CD4-dependent mechanism.
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.
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Ian R
IR
Humphreys
Andrea
A
Loewendorf
Carl
C
de Trez
Kirsten
K
Schneider
Chris A
CA
Benedict
Michael W
MW
Munks
Carl F
CF
Ware
Michael
M
Croft
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000628:therapy; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D053262:Receptors, OX40 / Q000172:deficiency / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D014764:Viral Proteins