Fate and function of anti-CD3/CD28-activated T cells following adoptive transfer: IL-2 promotes development of anti-tumor memory T cells in vivo.
BACKGROUND
Adoptive immunotherapy with T cells activated through CD3 alone requires exogenous IL-2 for T-cell function and survival after transfer, but the in vivo cytokine requirement of T cells activated through CD3 and CD28 is unknown. We hypothesized that CD3/CD28-activated T cells, unlike those activated through CD3 alone, might develop into long-lived memory T cells, either with or without systemic IL-2.


METHODS
We used MHC class I-restricted TCR transgenic T cells from the OT-1 mouse, specific for the surrogate tumor Ag ovalbumin (OVA), to assess the trafficking kinetics, antigenic responsiveness and anti-tumor efficacy of dual-activated T cells in vivo as a function of IL-2 administration. At days 7, 14, and 28 after transfer, lymph node cells and splenocytes were examined for donor cell persistence and antigenic responsiveness by FACS and ELISA, respectively.


RESULTS
In IL-2-treated mice, donor CD8+ T cells persisted and developed a memory phenotype, based on CD44 and Ly6c expression at day 28, while mice given no IL-2 had fewer donor cells at all time points. OVA-specific release of IFN-gamma was higher from lymphocytes of IL-2-treated mice compared with no-IL-2 mice (P<0.02 at all time points). In mice challenged with an OVA-bearing subline of the AML leukemia model C1498, IL-2 did not confer added protection from tumor challenge at 1 or 2 weeks after adoptive transfer, but gave improved survival at 4 weeks post-transfer.


CONCLUSIONS
We conclude that exogenous IL-2 is not required for anti-tumor activity of CD3/CD28-activated CD8+ cells early after adoptive transfer, but promotes T-cell persistence that confers disease protection at more remote times.
Hughes
D P M
DP
Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Baskar
D
D
Urban
F F
FF
Friedman
M S
MS
Braun
T M
TM
McDonagh
K T
KT
D000208:Acute Disease; D000818:Animals; D017951:Antigen Presentation; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D007700:Kinetics; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D007371:Interferon-gamma