"NK cell memory and help in HIV infection" 

Public Health/Infectious Diseases and Microbiology

Committee:
Robbie Maillard (advisor)
Simon Barratt-Boyes
Charles Rinaldo
Walt Storkus
Diana Metes

Abstract:

While natural killer (NK) cells are lauded for their killing effector function, they also play a critical role as immune helper cells, responding with great flexibility to environmental cues to provide subsequent alarm signals crucial for shaping and regulating the adaptive immune response. Most recently, the concept of immunological memory has been extended to NK cells, with the emergence of an inflated population of NK cells deficient in FcRg (FcRg⁻) described in the setting of HIV-1 infection. The physiological relevance of FcRg⁻ NK cells, including their relationship with HIV-1-associated chronic inflammatory events, and their potential to be targeted to improve HIV-1 control, are poorly understood. Here, I present an in-depth analysis of the impact of chronic HIV-1 infection and long-term antiretroviral therapy (ART) on the phenotypic and functional character of NK cells, with particular attention directed toward characterizing FcRg⁻ NK cells and exploring the reciprocal crosstalk between NK cells and dendritic cells (DCs) to enhance cellular-mediated immunity to HIV-1. Although NK cells are capable of providing immune help in response to innate stimuli during ART-mediated viral suppression, HIV-1 infection accelerates the expansion of highly differentiated FcRg⁻ NK ‘effector’ memory cells with limited function. By specializing in antibody-specific responses, FcRg⁻ NK cells compromise their responsiveness to DC-derived innate stimuli, leading to qualitative differences in their helper function and crosstalk with DCs. However, the potential exists for exploiting the inflated populations of FcRg⁻ NK cells in chronic HIV-1 infection to facilitate the induction of DC-mediated cellular immunity to HIV-1 via broadly neutralizing HIV-1-specific monoclonal antibodies (bNAbs) due to their superior antibody-dependent reactivity. Improving our understanding of the specialized nature of FcRg⁻ memory-like NK cells will be imperative for optimizing interventions to improve health outcomes and the effectiveness of HIV-1 therapies.