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.
Sportès
Claude
C
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. csportes@mail.nih.gov
Hakim
Frances T
FT
Memon
Sarfraz A
SA
Zhang
Hua
H
Chua
Kevin S
KS
Brown
Margaret R
MR
Fleisher
Thomas A
TA
Krumlauf
Michael C
MC
Babb
Rebecca R
RR
Chow
Catherine K
CK
Fry
Terry J
TJ
Engels
Julie
J
Buffet
Renaud
R
Morre
Michel
M
Amato
Robert J
RJ
Venzon
David J
DJ
Korngold
Robert
R
Pecora
Andrew
A
Gress
Ronald E
RE
Mackall
Crystal L
CL
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