Adaptive NKG2C+CD57+ Natural Killer Cell and Tim-3 Expression During Viral Infections

Abstract

Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions—a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.

Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

“…1E). This role of HIV in driving inflammation and CD4 depletion is supported by a reversal in the levels of systemic inflammation markers (Galectin-9, sCD163) and CD4 T-cell counts (and subsets) 29 after HAART ( Fig. 2e; Supplementary Fig.…”

Data analysis to modeling to building theory in NK cell biology and beyond: How can computational modeling contribute?

“…used Wanderlust was to track development of immature CD56 bright NK cells in individuals infected with HCMV using CyTOF measurements. The study found NK cells from HCMV‐infected individuals showed an early loss of CD62L accompanied with an up‐regulation of NKG2C, CD57, CD85j, and Tim‐3 …”

“…The developmental trajectory is determined by finding the shortest path that connects the precursor cell to the end‐state. Kared et al . used Wanderlust was to track development of immature CD56 bright NK cells in individuals infected with HCMV using CyTOF measurements.…”

“…95 The developmental trajectory is determined by finding the shortest path that connects the precursor cell to the end-state. Kared et al 96 used…”

“…The study found NK cells from HCMV-infected individuals showed an early loss of CD62L accompanied with an up-regulation of NKG2C, CD57, CD85j, and Tim-3. 96 The challenge of trajectory reconstruction posed by the type (2) measurements ( Fig. 3B) are dealt with in many disciplines, for example, in physics, tracking fluid particles from snapshot data obtained from microscopy experiments 97 or, in computer science, tracking individuals from snapshot data obtained from video feeds.…”