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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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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Figure 4

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Frequency of alloantigen-specific cytokine-producing cells in recipients...
Frequency of alloantigen-specific cytokine-producing cells in recipients treated with early or delayed anti-ICOS mAb. BALB/c WT recipients transplanted with C57BL/6 grafts were sacrificed 10 days after transplantation and their spleen cells used as responders, while irradiated spleen cells from naive C57BL/6 mice were used as stimulators. Data represent mean ± SEM of triplicates from 3–5 animals per group. (a) IFN-γ. Early anti-ICOS mAb-treated recipients exhibited a similar frequency of alloreactive IFN-γ–producing T cells as untreated recipients, while delayed anti-ICOS mAb-treated mice had significantly increased frequencies (P = 0.0115 versus untreated control). (b) IL-10. Both early and delayed ICOS blockade resulted in significantly reduced frequencies of IL-10–producing alloreactive T cells (P = 0.0047 for both early and delayed versus controls). (c) IL-4. Only delayed blockade produced a significant increase in the IL-4–producing frequencies (P = 0.0006 versus controls). (d) IL-4 production by splenocytes following ex vivo CD8+ depletion. There was a reduction in IL-4 frequencies following ex vivo CD8+ T cell depletion using splenocytes from both controls and delayed ICOS blockade groups, although this was only significant in the animals treated with delayed ICOS blockade (P = 0.0003 for CD8-depleted versus nondepleted sample for delayed blockade). Moreover, there was a significant difference between the CD8-depleted samples with a lower IL-4 frequency in the delayed-treatment group (P = 0.035 for CD8-depleted control versus CD8-depleted delayed-blockade group), demonstrating a higher frequency of IL-4–producing cells in the presence of CD8+ T cells and following delayed ICOS blockade. *P < 0.05; **P < 0.01; ***P < 0.001.