NK cell-mediated regulation of T cell immunity in TB/HIV co-infection

One third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and over 10 million are co-infected with human immunodeficiency virus (HIV). Latent Mtb infection (LTBI) represents immune containment, however HIV infection increases the risk of reactivation of LTBI from a 5-10% lifetime risk in HIV- uninfected individuals to a 10% annual risk in HIV-positive individuals. HIV-associated dysregulation of innate immunity and impairment of adaptive immunity by depletion of CD4 T helper cells likely contribute to loss of immune control of LTBI and progression to TB disease in HIV co-infected individuals. However, the parameters of immune control of LTBI that are perturbed in the setting of HIV co-infection have not been defined. Studies of Mtb infection in humans and animal models have demonstrated that both innate and adaptive immunity, particularly T cells, are critical for immune control of LTBI. Interestingly, recent evidence indicates innate immune cells play an important role in modulating antigen-specific T cell responses. Natural killer (NK) cells have been shown to modulate antigen-specific T cells by direct mechanisms, such as lysis of activated and/or antigen-specific CD4 and CD8 T cells, and indirect mechanisms, such as editing dendritic cell populations that prime effector T cell responses, and limiting the capacity of antigen presenting cells to stimulate antigen- specific T cell proliferation. Thus, innate immune cells can shape the profiles of antigen-specific T cell responses to a pathogen. The focus of this proposal is to examine how the innate immune response modulates Mtb-specific T cell immunity and determine how the regulatory pathways linking innate and adaptive immunity to Mtb are perturbed in the setting of HIV co-infection. We propose to test the hypotheses that (1) NK cells modulate the phenotype and functional profile of Mtb-specific memory T cells, and (2) that co-infection with HIV perturbs NK cell-mediated regulation of Mtb-specific memory T cell responses by promoting NK cell lysis of Mtb-specific CD4 and CD8 T cells, thereby contributing to loss of immune control of LTBI and increased risk of progression to TB disease in HIV/Mtb co-infected individuals. We propose to (1) define the phenotypic profiles, functional capacities, and NK cell receptor genotypes in persons with LTBI and HIV co-infection; (2) determine the relationship between NK cell profiles and the phenotype and function of Mtb-specific CD4 and CD8 T cell responses; and (3) define the direct and indirect mechanisms whereby NK cells modulate Mtb-specific CD4 and CD8 T cell immunity in LTBI, and how the mechanisms of cross-talk between NK cells and Mtb-specific T cells are dysregulated in the setting of HIV co-infection. Defining immune pathways involved in the generation, maintenance, and regulation of protective memory T cell responses to Mtb infection, and identifying the mechanisms whereby HIV infection impairs protective T cell immunity to Mtb, will be of vital importance to facilitate development of effective TB vaccines and targeted immunotherapeutic interventions and treatment of individuals co-infected with HIV and Mtb that are necessary to curb the TB epidemic worldwide.