T-cell dynamics after high-dose chemotherapy in adults: elucidation of the elusive CD8+ subset reveals multiple homeostatic T-cell compartments with distinct implications for immune competence.
Recovery of total T cell numbers after in vivo T-cell depletion in humans is accompanied by complex perturbation within the CD8+ subset. We aimed to elucidate the reconstitution of CD8+ T cells by separate analysis of putative naïve CD95- CD28+, memory CD95+ CD28+ and CD28- T cell compartments after acute maximal depletion by high-dose chemotherapy (HD-ChT) in women with high-risk breast cancer. We found that recovery of putative naïve CD8+ CD95- CD28+ and CD4+ CD95- CD28+ T cells, was compatible with a thymus-dependent regenerative pathway since their recovery was slow and time-dependent, their values were tightly related to each other, and their reconstitution patterns were inversely related to age. By analysing non-naïve T cells, a striking diversion between putative memory T cells and CD28- T cells was found. These latter increased early well beyond normal values, thus playing a pivotal role in total T-cell homeostasis, and contributed to reduce the CD4 : CD8 ratio. In contrast, putative memory T cells returned to values not significantly different from those seen in patients at diagnosis, indicating that this compartment may recover after HD-ChT. At 3-5 years after treatment, naïve T cells persisted at low levels, with expansion of CD28- T cells, suggesting that such alterations may extend further. These findings indicate that CD28- T cells were responsible for 'blind' T-cell homeostasis, but support the notion that memory and naïve T cells are regulated separately. Given their distinct dynamics, quantitative evaluation of T-cell pools in patients undergoing chemotherapy should take into account separate analysis of naïve, memory and CD28- T cells.
Fagnoni
Francesco F
FF
Medical Oncology Division and Surgery Division, Scientific Institute of Pavia, Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione, IRCCS, Pavia, Italy. ffagnoni@fsm.it
Lozza
Laura
L
Zibera
Carlo
C
Zambelli
Alberto
A
Ponchio
Luisa
L
Gibelli
Nadia
N
Oliviero
Barbara
B
Pavesi
Lorenzo
L
Gennari
Roberto
R
Vescovini
Rosanna
R
Sansoni
Paolo
P
Da Prada
Gianantonio
G
Robustelli Della Cuna
Gioacchino
G
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D018106:CD28 Antigens / Q000032:analysis; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002469:Cell Separation / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000187:drug effects
D018106:CD28 Antigens