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.
Humphreys
Ian R
IR
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Loewendorf
Andrea
A
de Trez
Carl
C
Schneider
Kirsten
K
Benedict
Chris A
CA
Munks
Michael W
MW
Ware
Carl F
CF
Croft
Michael
M
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