The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity
Hiroshi Harada, … , Gordon J. Freeman, Mohamed H. Sayegh
Hiroshi Harada, … , Gordon J. Freeman, Mohamed H. Sayegh
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):234-243. https://doi.org/10.1172/JCI17008.
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Article

The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity

Abstract

Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility–mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility–mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10–producing cells and an increased frequency of both IFN-γ– and IL-4–producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription–6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.

Authors

Hiroshi Harada, Alan D. Salama, Masayuki Sho, Atsushi Izawa, Sigrid E. Sandner, Toshiro Ito, Hisaya Akiba, Hideo Yagita, Arlene H. Sharpe, Gordon J. Freeman, Mohamed H. Sayegh

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The effect of ICOS-B7h blockade on effector CD8+ T cell generation and a...
The effect of ICOS-B7h blockade on effector CD8+ T cell generation and alloantibody production. (a and b) Percentages of effector CD8+ T cells. Splenocytes obtained from transplant recipients were used for staining of effector CD8+ T cells, characterized as CD8+CD44high CDD62Llow cells. The scatter plots are shown in (b). The population of effector CD8+ cells (gated in R3) in the early anti-ICOS treatment group is as high as that of the untreated controls (a). However, the number of effector CD8+ T cells was significantly suppressed in the delayed-treatment group. The representative data among three different experiments is expressed as the mean percentage ± SEM, run in triplicates (*P < 0.005 as compared with the untreated control or the early anti-ICOS mAb treatment group). (c and d) Alloantibody production in allograft recipients treated with delayed ICOS-B7h blockade. Naive donor strain C57BL/6 splenocytes were incubated with serum from transplant recipients obtained 10 days after transplantation. Binding of alloantibody was assessed by flow cytometry analysis after incubation of FITC-conjugated rat anti-mouse IgG2a (c) or anti-mouse IgG1 (d) antibody. The percentage of donor cells binding at each serum dilution from three individual recipients per group is expressed. Production of alloantibody was observed in the sera of the untreated control recipients, whereas delayed anti-ICOS mAb treatment drastically inhibited the production of IgG1 and IgG2a alloantibodies (P < 0.01 as compared with untreated controls). Similar reduction was seen in the early-treatment group (data not shown). 1/dilution, reciprocal of dilution, i.e., 50 = 1 in 50 dilution.