Suppressing to sustain : immune regulatory roles of sphingosine kinase 2 and CD22 in viral persistence
Chronic viral infections pose significant challenges to host immunity, often leading to viral persistence and suppressed immune responses. These infections are characterized by prolonged antigen exposure, progressive T cell dysfunction, and complex interactions between innate and adaptive immune compartments. While extensive research has delineated mechanisms of CD8⁺ T cell exhaustion, the molecular pathways governing the suppression of CD4⁺ T cells and innate immune cells in chronic viral infection remain incompletely understood. Moreover, the role of metabolic signaling in shaping immune responses during chronic infection is increasingly recognized but poorly defined. Sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid metabolism, has emerged as a potential metabolic checkpoint that integrates immune regulation with host antiviral responses. Using the chronic lymphocytic choriomeningitis virus (LCMV) Clone 13 infection mouse model, this dissertation investigates the dual role of SphK2 in modulating immune responses across both the adaptive and innate compartments. The first part focuses on CD22, one of the downstream regulators of SphK2, identifying the SphK2-CD22 axis as an important pathway that suppresses virus-specific CD4⁺ T cell proliferation and effector function. The second part examines SphK2-mediated control of innate immunity, revealing that neutrophils acquire suppressive phenotypes under the influence of SphK2, thereby partially limiting immune-mediated pathology. These studies collectively demonstrate that SphK2 functions as a central metabolic regulator that coordinates T cell-intrinsic and myeloid cell-mediated immune pathways during chronic viral infection. By integrating functional immunological assays, adoptive transfer experiments, and transcriptomic analyses, this work provides mechanistic insights into how SphK2 intersects with immune suppression and viral persistence. Understanding these pathways may inform the development of novel therapeutic strategies aimed at restoring antiviral immunity while minimizing immunopathology in chronic viral diseases.