Analysis of expression and function of the costimulatory molecule 4-1BB in alloimmune responses.
BACKGROUND
4-1BB (CD137) is a T cell costimulatory molecule that promotes T cell activation. In this study, we investigated the role of 4-1BB costimulation in allogeneic T cell responses.


METHODS
Vascularized heart transplantation, allogeneic mixed leukocyte reaction (MLR), and graft versus host disease models were used to examine 4-1BB and 4-1BBL expression. In addition, agonistic anti-4-1BB antibodies were used in MLR to functionally analyze T cell responses.


RESULTS
Using a heart transplant model, we found that 4-1BB and 4-1BBL transcripts were both expressed in rejecting cardiac grafts. In the allogeneic MLR, 4-1BB was expressed on both activated CD4 and CD8 T cells and 4-1BB was expressed on T cells after multiple cell divisions in vivo. Functionally, 4-1BB was a potent stimulator of proliferation, cytokine secretion, and CD25 expression by CD8 T cells, but 4-1BB signals had a weak effect on the proliferation of CD4 T cells. Because 4-1BB promoted the secretion of IL-2 and the expression of CD25 on CD8 T cells, we investigated whether IL-2 was the only factor whereby 4-1BB signals induced CD8 T cell proliferation. Although IL-2 was required for optimal CD8 T cell proliferation, 4-1BB also costimulated CD8 T cell proliferation independently of IL-2.


CONCLUSIONS
This study demonstrates that 4-1BB is expressed on activated, maximally divided T cells and shows that 4-1BB promotes CD8 T cell proliferation by enhancing signals through the IL-2 receptor and by other mechanisms independent of the IL-2 pathway.
The Carlos and Marguerite Mason Transplantation Biology Research Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
J T
JT
Tan
J
J
Ha
H R
HR
Cho
C
C
Tucker-Burden
R C
RC
Hendrix
R S
RS
Mittler
T C
TC
Pearson
C P
CP
Larsen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD; D016207:Cytokines / Q000096:biosynthesis; D016027:Heart Transplantation / Q000276:immunology; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9