Characterization of Galectin-9+ and TIGIT+ Natural Killer Cells in Human Immunodeficiency Virus-1 Infected Individuals

Abstract

NK cells play an integral role in mediating immune responses to viral infections; however, their function is compromised during chronic diseases such as HIV-1, partly due to an increase in expression of inhibitory receptors. Thus, one of the reasons for the reduced immune responses elicited by NK cells in HIV infection, can be the result of engagement of co-inhibitory molecules with their respective ligands. Galectin-9 (Gal-9) is a tandem-repeat type galectin that possesses a wide range of immunomodulatory properties such as interaction with Tim-3, which is upregulated on T cells during chronic conditions. Previously, our group has shown that interaction of Gal-9 on regulatory T cells with Tim-3 on CD8+ T cells renders them more permissible to immunosuppression and subsequently leads to their exhaustion. Thus, we aimed to further study the role of Gal-9 on NK cell function in HIV-infected patients. As a comparison, we also analyzed another inhibitory receptor known as TIGIT. Our data indicates upregulation of surface Gal-9 and TIGIT on NK cells in HIV-infected individuals on antiretroviral therapy, long-term non-progressors and progressors compared to healthy controls. We observed two effector NK cell populations with dichotomous functional potential. TIGIT+ NK cells expressed more cytotoxic molecules (GzmB, perforin and granulysin) but less IFN-γ. Conversely, Gal-9+ NK cells expressed less cytotoxic molecules, but more IFN-γ. Additionally, Gal-9+ NK cells, in contrast to Gal-9- NK cells, co-expressed negligible amounts of GzmB and perforin, which is detrimental to their cytotoxic abilities. However, the functional potential of these Gal-9+ NK cells can be augmented, as the addition of a cytokine cocktail (IL-12, IL-15 and IL-18) enhanced their degranulation and expression of effector molecules. We believe that understanding the underlying pathway associated with Gal-9+ NK cells differential functional potential, can pave the way for potential therapeutic strategies.