Acquisition of polyfunctionality by Epstein-Barr virus-specific CD8+ T cells correlates with increased resistance to galectin-1-mediated suppression.
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 virus-infected 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 gammaC cytokine, interleukin-2, restored polyfunctionality and shielded these cells from the inhibitory effects of galectin-1.
Division of Immunology, Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
Corey
C
Smith
Leone
L
Beagley
Rajiv
R
Khanna
D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000494:pharmacology; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D037483:Galectin 1 / Q000276:immunology / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D014763:Viral Matrix Proteins / Q000276:immunology
D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D037483:Galectin 1; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D014763:Viral Matrix Proteins; C417029:EBV-encoded nuclear antigen 1