OX40 ligation of CD4+ T cells enhances virus-specific CD8+ T cell memory responses independently of IL-2 and CD4+ T regulatory cell inhibition.
We have previously shown that CD4(+) T cells are required to optimally expand viral-specific memory CD8(+) CTL responses using a human dendritic cell-T cell-based coculture system. OX40 (CD134), a 50-kDa transmembrane protein of the TNFR family, is expressed primarily on activated CD4(+) T cells. In murine models, the OX40/OX40L pathway has been shown to play a critical costimulatory role in dendritic cell/T cell interactions that may be important in promoting long-lived CD4(+) T cells, which subsequently can help CD8(+) T cell responses. The current study examined whether OX40 ligation on ex vivo CD4(+) T cells can enhance their ability to "help" virus-specific CTL responses in HIV-1-infected and -uninfected individuals. OX40 ligation of CD4(+) T cells by human OX40L-IgG1 enhanced the ex vivo expansion of HIV-1-specific and EBV-specific CTL from HIV-1-infected and -uninfected individuals, respectively. The mechanism whereby OX40 ligation enhanced help of CTL was independent of the induction of cytokines such as IL-2 or any inhibitory effect on CD4(+) T regulatory cells, but was associated with a direct effect on proliferation of CD4(+) T cells. Thus, OX40 ligation on CD4(+) T cells represents a potentially novel immunotherapeutic strategy that should be investigated to treat and prevent persistent virus infections, such as HIV-1 infection.
Yu
Qigui
Q
Clinical Sciences Division, University of Toronto, Ontario, Canada.
Yue
Feng Yun
FY
Gu
Xiao X
XX
Schwartz
Herbert
H
Kovacs
Colin M
CM
Ostrowski
Mario A
MA
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D053278:OX40 Ligand; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000276:immunology
D007376:Interleukin-2; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D015375:Receptors, Interleukin-2; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; D048069:Tumor Necrosis Factors