Cytomegalovirus Infection Leads to Development of High Frequencies of Cytotoxic Virus-Specific CD4+ T Cells Targeted to Vascular Endothelium.
Cytomegalovirus (CMV) infection elicits a very strong and sustained intravascular T cell immune response which may contribute towards development of accelerated immune senescence and vascular disease in older people. Virus-specific CD8+ T cell responses have been investigated extensively through the use of HLA-peptide tetramers but much less is known regarding CMV-specific CD4+ T cells. We used a range of HLA class II-peptide tetramers to investigate the phenotypic and transcriptional profile of CMV-specific CD4+ T cells within healthy donors. We show that such cells comprise an average of 0.45% of the CD4+ T cell pool and can reach up to 24% in some individuals (range 0.01-24%). CMV-specific CD4+ T cells display a highly differentiated effector memory phenotype and express a range of cytokines, dominated by dual TNF-α and IFN-γ expression, although substantial populations which express IL-4 were seen in some donors. Microarray analysis and phenotypic expression revealed a profile of unique features. These include the expression of CX3CR1, which would direct cells towards fractalkine on activated endothelium, and the β2-adrenergic receptor, which could permit rapid response to stress. CMV-specific CD4+ T cells display an intense cytotoxic profile with high level expression of granzyme B and perforin, a pattern which increases further during aging. In addition CMV-specific CD4+ T cells demonstrate strong cytotoxic activity against antigen-loaded target cells when isolated directly ex vivo. PD-1 expression is present on 47% of cells but both the intensity and distribution of the inhibitory receptor is reduced in older people. These findings reveal the marked accumulation and unique phenotype of CMV-specific CD4+ T cells and indicate how such T cells may contribute to the vascular complications associated with CMV in older people.
University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom.
Annette
A
Pachnio
University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom.|Oncohematology Research Group, Navarrabiomed-Fundación Miguel Servet, IDISNA (Navarra's Health Research Institute), Pamplona, Spain.
Miriam
M
Ciaurriz
University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom.
Jusnara
J
Begum
University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom.
Neeraj
N
Lal
University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom.
Jianmin
J
Zuo
University of Birmingham, College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Edgbaston, Birmingham, United Kingdom.
Andrew
A
Beggs
University of Birmingham, College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, Edgbaston, Birmingham, United Kingdom.
Paul
P
Moss
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
C573415:IFNG protein, human; C508598:IL4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma