The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity
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
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 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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Expansion and apoptosis of alloreactive CD4+ T cells after ICOS-B7h bloc...
Expansion and apoptosis of alloreactive CD4+ T cells after ICOS-B7h blockade. After adoptive transfer of transgenic ABM CD4+ T cells into nude mice, the animals were transplanted with bm12 skin and left untreated or were given anti-ICOS mAb according to the two protocols. Ten days later, draining lymph nodes were removed and the number of alloreactive CD4+ T cells was examined (a). To control for homeostatic proliferation, some animals were adoptively transferred with cells but received no transplant (AT only), and these demonstrated only modest proliferation. By comparison, there was a marked expansion of CD4+ T cells after transplantation, which was significantly reduced after early and delayed ICOS-B7h blockade (by 54% and 53%, respectively; ***P < 0.0001 for either as compared with transplant controls). (b) By gating on the transgenic CD4+ T cells, the percentage of alloreactive cells undergoing apoptosis was measured by annexin V staining. There was no difference in the percentage of cells undergoing apoptosis between controls and early or delayed blockade, demonstrating that the reduction in expansion after ICOS-B7h blockade was not simply due to increased apoptosis. FL2-H, annexin V.