title: Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy.
abstract: Rapid recovery of CD4+ T cells after intensive chemotherapy is limited by an age-dependent decline in thymopoiesis. Here we sought to determine whether similar limitations exist for CD8+ T-cell regeneration. After intensive chemotherapy, CD8+ T cells had a faster effective doubling time than CD4+ T cells (median, 12.6 v 28.2 days, P < .05). Accordingly, at 3 months posttherapy, mean CD8+ T-cell number had returned to baseline, whereas mean CD4+ T-cell number was only 35% of pretherapy values (P < .05). These differences were primarily due to very rapid expansion of CD8+CD57+ and CD8+CD28- subsets. At 3 months posttherapy, there was no relationship between age and CD8+ T-cell number (R = -.02), whereas CD4+ T-cell number was inversely related to age (R = -.66) and there were no discernible differences in CD8+ recovery among patients with or without thymic enlargement, whereas CD4+ recovery was enhanced in patients with thymic enlargement after chemotherapy (P < .01). Therefore thymic-independent pathways of T-cell regeneration appear to rapidly regenerate substantial numbers of CD8+, but not CD4+ T cells, resulting in prolonged T-cell subset imbalance after T-cell depletion. These inherent distinctions between CD4+ v CD8+ T-cell regeneration may have significant implications for immunotherapeutic strategies undertaken to eradicate minimal residual neoplastic disease after cytoreductive chemotherapy.
authors.affiliation: Laboratory of Mathematical Biology, National Cancer Institute, and the Clinical Pathology Department, National Institutes of Health, Bethesda, MD 20892-1928, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Mackall
authors.forename: T A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: M R
authors.initials: MR
authors.lastname: Brown
authors.forename: M P
authors.initials: MP
authors.lastname: Andrich
authors.forename: C C
authors.initials: CC
authors.lastname: Chen
authors.forename: I M
authors.initials: IM
authors.lastname: Feuerstein
authors.forename: I T
authors.initials: IT
authors.lastname: Magrath
authors.forename: L H
authors.initials: LH
authors.lastname: Wexler
authors.forename: D S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: R E
authors.initials: RE
authors.lastname: Gress
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007223:Infant; D018655:Lymphocyte Count / Q000187:drug effects*; D008231:Lymphopenia / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000276:immunology; D018365:Neoplasm, Residual; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology