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OX40 Ligation of CD4⁺ T Cells Enhances Virus-Specific CD8⁺ T Cell Memory Responses Independently of IL-2 and CD4⁺ T Regulatory Cell Inhibition¹

Qigui Yu^*, Feng Yun Yue^*, Xiao X. Gu^*, Herbert Schwartz, Colin M. Kovacs and Mario A. Ostrowski^2,*,

^* Clinical Sciences Division, University of Toronto, Toronto, Ontario, Canada; St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; Canadian Immunodeficiency Research Collaborative, Toronto, Ontario, Canada; and Department of Physiology, National University of Singapore, Singapore

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.

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