Acquisition of Polyfunctionality by Epstein-Barr Virus-Specific CD8 ⁺ T Cells Correlates with Increased Resistance to Galectin-1-Mediated Suppression

Abstract

Latent membrane antigen 1 and -2 (LMP-1/2)-specific CD8؉ T cells from newly diagnosed and relapsed Hodgkin's lymphoma (HL) patients display a selective functional impairment. In contrast, CD8؉ T cells specific for Epstein-Barr virus (EBV) nuclear proteins and lytic antigens retain normal T-cell function. Reversion to a dysfunctional phenotype of LMP-1/2-specific T cells is coincident with the regression of HL. To delineate the potential basis for this differential susceptibility for the loss of function, we have carried out a comprehensive functional analysis of EBV-specific T cells using ex vivo multiparametric flow cytometry in combination with assessment of antigen-driven proliferative potential. This analysis revealed that LMP-1/2-specific T cells from healthy virus carriers display a deficient polyfunctional profile compared to that of T cells specific for epitopes derived from EBV nuclear proteins and lytic antigens. Furthermore, LMP-specific T-cells are highly susceptible to galectin-1-mediated immunosuppression and are less likely to degranulate following exposure to cognate peptide epitopes and poorly recognized endogenously processed epitopes from virusinfected B cells. More importantly, ex vivo stimulation of these T cells with an adenoviral vector encoding multiple minimal CD8 ؉ T-cell epitopes as a polyepitope, in combination with a ␥C cytokine, interleukin-2, restored polyfunctionality and shielded these cells from the inhibitory effects of galectin-1.

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…This is an important finding as previous studies have mainly focused on IFN-g-production to characterize EBV-specific T cells [15,[27][28][29]. In line with our results a substantial fraction of TNF 1 non IFN-g producing EBVspecific CD8 1 T cells was observed in one recent study [51]. Furthermore, Amyes et al…”

Proteomic analysis identifies galectin-1 as a predictive biomarker for relapsed/refractory disease in classical Hodgkin lymphoma

“…On the basis of gene-expression profiling, Gal-1 was found to be overexpressed in HRS cell lines and its secretion favored a Th2-type immune response characterized by high IL-4 and IL-13 secretion and promoted the expansion of CD4 ϩ CD25 ϩ FoxP3 ϩ regulatory T cells. 12 Moreover, exposure to recombinant Gal-1 inhibited proliferation and IFN-␥ secretion by EBV-specific T cells, 11 and T cells specific for EBV-LMP1 were much more susceptible to Gal-1-mediated immunosuppression than conventional T cells, 34 suggesting a critical role for Gal-1 in compromising cHL-specific immunity. Supporting these findings, Gal-1-deficient (Lgals1 Ϫ/Ϫ ) mice were found to be highly susceptible to Th1-and Th17-dependent inflammation compared with their wild-type counterparts.…”

Effective Treatment of Metastatic Forms of Epstein-Barr Virus–Associated Nasopharyngeal Carcinoma with a Novel Adenovirus-Based Adoptive Immunotherapy

“…16,17). Poor immunogenicity of these antigens and the subsequent induction of subdominant T-cell responses are likely to play a key role in promoting immunoevasion by EBV-positive malignant cells (18)(19)(20)(21).…”