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Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity

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Department of Anatomy and Cell Biology, University of Wuerzburg, Koellikerstr 6, 97070 Wuerzburg, Germany
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Cellular Technology Limited, 20521 Chagrin Blvd, Shaker Heights, OH 44022, USA
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Department of Anatomy I, University of Cologne, Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Eric O. Freed
Viruses 2015, 7(8), 4414-4437; https://doi.org/10.3390/v7082828
Received: 18 June 2015 / Revised: 15 July 2015 / Accepted: 27 July 2015 / Published: 6 August 2015
Most humans become infected with human cytomegalovirus (HCMV). Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the TH1, TH2, and TH17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC). Using the enzyme-linked Immunospotr assay (ELISPOT) that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN)- and/or interleukin (IL)-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of TH1, TH2, and TH17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN- and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the TH1, TH2, and TH17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails. View Full-Text
Keywords: Human cytomegalovirus (HCMV); Enzyme-Linked Immunospot assay (ELISPOT); CD4 T cells; cytokine secretion; kinetics Human cytomegalovirus (HCMV); Enzyme-Linked Immunospot assay (ELISPOT); CD4 T cells; cytokine secretion; kinetics
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Wunsch, M.; Zhang, W.; Hanson, J.; Caspell, R.; Karulin, A.Y.; Recks, M.S.; Kuerten, S.; Sundararaman, S.; Lehmann, P.V. Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity. Viruses 2015, 7, 4414-4437.

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