Dual Function of the NK Cell Receptor 2B4 (CD244) in the Regulation of HCV-Specific CD8+ T Cells

Abstract

The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control.

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 + T-cell immune responses in tuberculosis infection

“…Molecular mechanisms for CD244 modulation of T-cell responses in infections remain unknown, although CD244 appears to regulate NK cell function that correlates with HBV or HCV persistence in humans (40,41). In this study, we find that human TB can upregulate CD244 and CD244 signaling-related molecules in CD8 + T cells.…”

“…It has recently been shown that CD244 is expressed on virus-specific CD8 + T cells (9,(39)(40)(41) and that CD244 signaling correlates with viral persistence of hepatitis B virus (HBV) and HCV in humans (9,39,40). However, little is known about the molecular mechanism and consequence for CD244 regulation of T-cell effector functions during active TB infection.…”

Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection

“…This observation is well in line with our recent findings in patients with chronic hepatitis C where we also found that targeting two different costimulatory or coinhibitory receptors had no synergistic but rather counteractive effects. 30 Similarly, nonredundant roles for the CTLA-4 and PD-1 pathways have been described in driving T-cell exhaustion in chronic hepatitis B. 47 Overall, these data indicate an individual ''private'' costimulatory receptor usage of T-cells during viral infections.…”

“…Immune responses against HEV were studied in a total of 38 subjects including 19 healthy immunocompetent individuals and 19 immunocompromised organ recipients. The immunocompetent group included anti-HEVpositive (''exposed'') subjects (n ¼ 9; median age 32; range 26-66) and anti-HEV-negative (''no exposure'') individuals (n ¼ 10; median age 30; range [25][26][27][28][29][30][31][32][33][34][35][36][37]. The immunocompromised group included transplanted patients who developed chronic hepatitis E (n ¼ 7; median age 49; range 34-66) and transplanted patients who resolved HEV infection (n ¼ 12; median age 53; range 27-69).…”

“…All assays were performed as previously described. 29,30 For details, please see Supporting Information. Briefly, T-cell proliferation was studied with the carboxyfluorescein diacetate succinimidyl ester (CFSE) method after stimulating peripheral blood mononuclear cells (PBMCs) in vitro with HEV overlapping peptide pools spanning ORF2 and ORF3 regions of the genome.…”