IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates.
Interleukin-7 (IL-7) is important for thymopoiesis in mice and humans because IL-7 receptor alpha (IL-7Ralpha) mutations result in a severe combined immunodeficiency phenotype with severe thymic hypoplasia. Recent evidence has indicated that IL-7 also plays an important role as a regulator of T-cell homeostasis. Here we report the immunologic effects of recombinant human IL-7 (rhIL-7) therapy in normal and simian immunodeficiency virus (SIV)-infected nonhuman primates. Cynomolgus monkeys receiving 10 days of rhIL-7 showed substantial, reversible increases in T-cell numbers involving a dramatic expansion of both naive and nonnaive phenotype CD4(+) and CD8(+) subsets. Although IL-7 is known to have thymopoietic effects in mice, we observed marked declines in the frequency and absolute number of T-cell receptor excision circle-positive (TREC(+)) cells in the peripheral blood and dramatic increases in the percentage of cycling T cells in the peripheral blood as measured by Ki-67 expression (baseline less than 5% to approximately 50% after 6 days of therapy) and ex vivo bromodeoxyuridine (BrdU) incorporation. Similarly, moderately CD4- depleted SIV-infected macaques treated with rhIL-7 also had significant increases in peripheral blood CD4(+) and CD8(+) T cells following rhIL-7 therapy. Thus, rhIL-7 induces dramatic alterations in peripheral T-cell homeostasis in both T-cell-replete and T-cell-depleted nonhuman primates. These results further implicate IL-7 as a promising immunorestorative agent but illustrate that a major component of its immunorestorative capacity reflects effects on mature cells. These results also raise the possibility that IL-7 therapy could be used to temporarily modulate T-cell cycling in vivo in the context of immunotherapies such as vaccination.
Fry
Terry J
TJ
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. tf60y@nih.gov
Moniuszko
Marcin
M
Creekmore
Stephen
S
Donohue
Susan J
SJ
Douek
Daniel C
DC
Giardina
Steven
S
Hecht
Toby T
TT
Hill
Brenna J
BJ
Komschlies
Kristen
K
Tomaszewski
Joseph
J
Franchini
Genoveffa
G
Mackall
Crystal L
CL
D000818:Animals; D017252:CD3 Complex / Q000097:blood; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes; D006706:Homeostasis; D015851:Interleukin-7 / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000032:analysis; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D020395:Receptors, Interleukin-7 / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology
D017252:CD3 Complex; D015851:Interleukin-7; D019394:Ki-67 Antigen; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins