IL-15 induces alloreactive CD28(-) memory CD8 T cell proliferation and CTLA4-Ig resistant memory CD8 T cell activation.
The presence of CD28(-) memory CD8 T cells in the peripheral blood of renal transplant patients is a risk factor for graft rejection and resistance to CTLA-4Ig induction therapy. In vitro analyses have indicated poor alloantigen-induced CD28(-) memory CD8 T cell proliferation, raising questions about mechanisms mediating their clonal expansion in kidney grafts to mediate injury. Candidate proliferative cytokines were tested for synergy with alloantigen in stimulating CD28(-) memory CD8 T cell proliferation. Addition of IL-15, but not IL-2 or IL-7, to co-cultures of CD28(-) or CD28(+) memory CD8 T cells and allogeneic B cells rescued proliferation of the CD28(-) and enhanced CD28(+) memory T cell proliferation. Proliferating CD28(-) memory CD8 T cells produced high amounts of interferon gamma and tumor necrosis factor alpha and expressed higher levels of the cytolytic marker CD107a than CD28(+) memory CD8 T cells. CTLA-4Ig inhibited alloantigen-induced proliferation of CD28(+) memory CD8 T cell proliferation but had no effect on alloantigen plus IL-15-induced proliferation of either CD28(-) or CD28(+) memory CD8 T cells. These results indicate the ability of IL-15, a cytokine produced by renal epithelial during inflammation, to provoke CD28(-) memory CD8 T cell proliferation and to confer memory CD8 T cell resistance to CTLA-4Ig-mediated costimulation blockade.
Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH; Division of Nephrology, Department of Internal Medicine, Thammasart University, Pathumthani, Thailand.
O
O
Traitanon
A
A
Gorbachev
J J
JJ
Bechtel
K S
KS
Keslar
W M
WM
Baldwin
E D
ED
Poggio
R L
RL
Fairchild
D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000502:physiology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed
D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D019409:Interleukin-15
Costimulation; T cell biology; belatacept; cytokines/cytokine receptors; immunosuppressant