The Journal of Experimental Medicine
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Published online December 11, 2006
doi:10.1084/jem.20052246
The Journal of Experimental Medicine, Vol. 203, No. 13, 2865-2877
The Rockefeller University Press, 0022-1007 $30.00
© 2006 Casazza et al.
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ARTICLE

 Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation

Joseph P. Casazza1, Michael R. Betts1,4, David A. Price2, Melissa L. Precopio1, Laura E. Ruff2, Jason M. Brenchley2, Brenna J. Hill2, Mario Roederer3, Daniel C. Douek2, and Richard A. Koup1

1 Immunology Laboratory, 2 Human Immunology Section, and 3 Immunotechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892
4 Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104

CORRESPONDENCE Richard A. Koup: rkoup{at}mail.nih.gov

The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the cytokines interferon (IFN)-{gamma}, tumor necrosis factor (TNF)-{alpha}, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1ß, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1ß, TNF-{alpha}, and IFN-{gamma} in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.

Abbreviations used: B-LCL, B lymphoblastoid cell; CMTMR, chloromethyl-benzoyl-aminotetramethyl-rhodamine; MIP, macrophage inflammatory protein.


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