CMV is a common but problematic viral pathogen in solid organ transplantation, associated with higher risk of graft injury, graft rejection and patient morbidity and mortality. In this dissertation, we aimed to define the overall immune signatures of kidney transplant recipients experiencing CMV viremia, investigate how different CMV histories influence responses to viral reactivation, and explore the immune-modulating mechanisms through which CMV may contribute to adverse transplant outcomes. In Chapter 1, we provided an overview of CMV biology, transplant immunology, T cell phenotypes and characteristics and how they are inter-related. In Chapter 2, we used a systems immunology approach to provide a longitudinal immune profile of KTRs with or without CMV viremia. Immature CD56bright NK cells, platelet activation signatures, and elevated plasma IL-15, EGF, and sCD40L were predictive of CMV reactivation. Following CMV viremia, mature CD56dim NK cells and terminally differentiated CD28- CD8+ T cells expanded and continued to proliferate after one-year post-transplant. These CD28- CD8+ T cells expressed high levels of cytotoxic markers (GZMB, GNLY, NKG7) and NK-associated receptors like CD16. Both mature NK cells and CD28- CD8+ T cells were linked to effective control of CMV, helping prevent prolonged viremia and high viral loads. In Chapter 3, We investigated CD8+ T cells at the single-cell level and uncovered their differentiation dynamics in response to CMV infection. We found that CD8+ T cells in KTRs with CMV infection appeared as a continuum driven by history of CMV exposure and provided insights into the transcriptional regulation that influenced the generation of CD8+ T cell immunity to CMV following primary infection. We also identified CD8+ T cells of CD28lo KLRG1hi IL-7Rlo HLA-DRhi phenotypes distinguishing patients who resisted or developed viremia post-transplant. These cells were not end-stage effectors and retained the potential to expand upon CMV reactivation for long-term immune surveillance, serving as potential key biomarkers for patient infection risk stratification. In Chapter 4, we examined CD16+ CD8+ T cells and their relationship with CMV. While CD16 is typically found on NK cells, we demonstrated that IL-15 can induce CD16 expression on CD8+ T cells in an antigen-independent manner, with further upregulation through TCR co-stimulation. These CD16+ CD8+ T cells acquired innate ADCC functions similar to NK cells, and their frequency was elevated in CMV viremic patients, particularly in those with poor control of the virus. We propose a model where IL-15, induced by CMV infection, drives CD16 expression on CD8+ T cells, contributing to antibody-mediated rejection via donor-specific antibody-CD16 engagement. Chapter 5 concluded the dissertation, proposed a model of CD8+ T cell immune modulation as a result of CMV in transplant recipients, and shed light to potential future investigations associated with CMV and solid organ transplantation.