The Journal of Experimental Medicine
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Published online June 23, 2008
doi:10.1084/jem.20071681
The Journal of Experimental Medicine, Vol. 205, No. 7, 1701-1714
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Sportès et al.
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ARTICLE

 Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets

Claude Sportès1, Frances T. Hakim1, Sarfraz A. Memon1, Hua Zhang2, Kevin S. Chua2, Margaret R. Brown4, Thomas A. Fleisher4, Michael C. Krumlauf1, Rebecca R. Babb1, Catherine K. Chow3, Terry J. Fry2, Julie Engels5, Renaud Buffet5, Michel Morre5, Robert J. Amato6, David J. Venzon7, Robert Korngold8, Andrew Pecora8, Ronald E. Gress1, and Crystal L. Mackall2

1 Experimental Transplantation and Immunology Branch; 2 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute; 3 Departments of Radiology; 4 Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892
5 Cytheris Inc., Rockville, MD 20850
6 Methodist Hospital, Texas Medical Center, Houston, TX 77021
7 Biostatistics and Data Management Section, National Cancer Institute, 8 The Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601

CORRESPONDENCE Claude Sportès: csportes{at}mail.nih.gov

Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4+ and CD8+ T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8+ effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.

Abbreviations used: CT, computerized tomography; {gamma}c, common {gamma} chain; rh, recombinant human; MFI, mean fluorescence intensity; RTE, recent thymic emigrant; TREC, TCR excision circle.

R.E. Gress and C.L. Mackall contributed equally to this paper.


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