Enhancement of Human Immunodeficiency Virus-Specific CD8+ T Cell Responses with TIGIT Blockade Involves Trogocytosis.

Abstract

Natural killer (NK) and CD8⁺ T cell function is compromised in human immunodeficiency virus type 1 (HIV-1) infection by increased expression of inhibitory receptors such as TIGIT (T cell immunoreceptor with Ig and ITIM domains). Blocking inhibitory receptors or their ligands with monoclonal antibodies (mAb) has potential to improve antiviral immunity in general and facilitate HIV eradication strategies. We assessed the impact of TIGIT engagement and blockade on cytotoxicity, degranulation, and interferon-gamma (IFN-γ) production by CD8⁺ T cells from persons living with HIV (PLWH). The effect of TIGIT engagement on non-specific anti-CD3-redirected cytotoxicity was assessed in redirected cytotoxicity assays, and the effect of TIGIT blockade on HIV-specific CD8⁺ T cell responses was assessed by flow cytometry. In 14/19 cases where peripheral blood mononuclear cells (PBMC) mediated >10% redirected cytotoxicity, TIGIT engagement reduced the level of cytotoxicity to <90% of control values. We selected PLWH with >1000 HIV Gag or Nef-specific IFN-γ spot forming cells per million PBMC to quantify the effects of TIGIT blockade on HIV-specific CD8⁺ T cell responses by flow cytometry. Cell surface TIGIT expression decreased on CD8⁺ T cells from 23/40 PLWH following TIGIT blockade and this loss was associated with increased anti-TIGIT mAb fluorescence on monocytes. In total, 6 of these 23 PLWH had enhanced HIV-specific CD8⁺ T cell degranulation and IFN-γ production with TIGIT blockade, compared to 0/17 with no decrease in cell surface TIGIT expression. Reduced CD8⁺ T cell TIGIT expression with TIGIT blockade involved trogocytosis by circulating monocytes, suggesting that an effector monocyte population and intact fragment crystallizable (Fc) functions are required for mAb-based TIGIT blockade to effectively enhance HIV-specific CD8⁺ T cell responses.