title: Phenotypic and transcriptional profile correlates with functional plasticity of antigen-specific CD4+ T cells.
abstract: The role of CD4(+) T cells in the control of infectious pathogens is highly complex with a myriad of functions but how these T cells acquire differential functional potentiality remains poorly defined. Here we show that human cytomegalovirus (CMV)-specific CD4(+) T cells directed towards different viral antigens expressed predominantly TNF-α alone or TNF-α and IFN-γ. TNF-α(+) and IFN-γ(+) CD4(+) T cells expressed significantly higher levels of T-box transcription factors T-bet with graded loss of Eomesodermin (Eomes) expression (T-bet(Hi)Eomes(Hi/Lo)) when compared with TNF-α(+) CD4(+) T cells expressing lower levels of both T-bet and Eomes (T-bet(-)Eomes(-)). Furthermore, TNF-α(+) and IFN-γ(+) CD4(+) T cells expressed significantly higher levels of perforin and interleukin (IL)-2 and displayed a terminally differentiated phenotype (CCR7(-)CD27(-)CD45RA(-)CD57(+)CD62L(-)). In contrast, TNF-α(+) alone CMV-specific CD4(+) T cells were predominantly early-memory phenotype with a proportion of these cells displaying T memory stem-cell phenotype (CD95(+)CD45RA(+)CCR7(+)CD27(+)). In vitro stimulation of CMV-specific CD4(+) T cells with viral antigen in the presence of IL-12 was sufficient to dramatically change the transcriptional and functional profile of TNF-α(+) CD4(+) T cells, whereas TNF-α(+) and IFN-γ(+) CD4(+) T cells remained unaltered. These findings illustrate an intrinsic link between cytokine expression, transcriptional regulation and cellular differentiation, and their impact on functional plasticity of virus-specific CD4(+) T cells.
authors.affiliation: Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory, Department of Immunology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Emily S J
authors.initials: ES
authors.lastname: Edwards
authors.affiliation: Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory, Department of Immunology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Corey
authors.initials: C
authors.lastname: Smith
authors.affiliation: Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory, Department of Immunology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000328:Adult; D000943:Antigens, Differentiation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008875:Middle Aged; D014158:Transcription, Genetic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D000956:Antigens, Viral; C573415:IFNG protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma