Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.
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.
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. csportes@mail.nih.gov
Claude
C
Sportès
Frances T
FT
Hakim
Sarfraz A
SA
Memon
Hua
H
Zhang
Kevin S
KS
Chua
Margaret R
MR
Brown
Thomas A
TA
Fleisher
Michael C
MC
Krumlauf
Rebecca R
RR
Babb
Catherine K
CK
Chow
Terry J
TJ
Fry
Julie
J
Engels
Renaud
R
Buffet
Michel
M
Morre
Robert J
RJ
Amato
David J
DJ
Venzon
Robert
R
Korngold
Andrew
A
Pecora
Ronald E
RE
Gress
Crystal L
CL
Mackall
D000367:Age Factors; D000818:Animals; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006678:HIV / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000276:immunology; D006801:Humans; D015851:Interleukin-7 / Q000008:administration & dosage* / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C508605:IL7 protein, human; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins