Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2024

Is BTN3A1 a regulator of αβ T cell responses? (#167)

Kezia Christilla Singgih 1 , Rachel Deanne Pascoe 1 2 , Caroline Soliman 1 , Shihan Li 1 , Zheng Ruan 1 , Dale Godfrey 1 , Celine Gubser 3 4 , Sharon Lewin 1 2 3 5 , Adam Uldrich 1 , Tom Fulford 1
  1. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia
  2. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
  3. Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia
  4. Service des Maladies Infectieuses, CHUV, Lausanne, Switzerland
  5. Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia

The role of butyrophilins (BTNs) as mediators of human γδ T cell activation has been well-characterised. However, a recent study reported that the overexpressed BTN member 3A1 (BTN3A1) on ovarian cancer tumours may suppress human CD4+ and CD8+ αβ T cell responses through engagement with CD45RO. BTN3A1 has also been shown to be elevated in chronic HIV infection with an overexpression of BTN3A1 on CD4+ T cells enriched with total HIV DNA, and when coupled with persisting impaired HIV-specific CD8+ T cell responses, may suggest a role for BTN3A1 in facilitating impaired HIV-specific responses. We, therefore, aimed to elucidate the potential immunosuppressive role of BTN3A1 towards CD4+ and CD8+ αβ T cells, and investigate the therapeutic benefits of disrupting BTN3A1 interactions with BTN3A-directed neutralising monoclonal antibodies (mAbs) to reinvigorate HIV-specific CD8+ T cell immunity in vitro. Using a redirected presentation assay, we were not able to demonstrate BTN3A1-mediated suppression of CD4+ and CD8+ αβ T cell activation, proliferation, cytokine secretion and cytotoxicity. In line with these findings, treatment of peripheral blood mononuclear cells from people living with HIV on suppressive antiretroviral therapy with anti-BTN3A blocking mAbs failed to reinvigorate HIV-specific CD8+ T cell cytotoxicity and proliferative capacity. Furthermore, we failed to observe an interaction between BTN3A1 and CD45RO ectodomains using tetramers. Collectively, our findings are inconsistent with the concept that BTN3A1 can suppress CD4+ and CD8+ αβT cells in vitro or in HIV infection, and moreover, we were unable to detect an interaction between BTN3A1 and CD45RO in contrast to a previous report. The reasons for the discrepancy in results are currently unclear and further studies are required to establish whether targeting BTNs with agonist or antagonist mAbs confer any therapeutic benefit for αβ T cell responses in acute or chronic viral infections.