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.

Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo

“…The technique for ELISPOT analysis has been described recently by our group and others (37)(38)(39). Immunospot plates (Cellular Technology) were coated with 4 g/ml rat anti-mouse IFN-␥ mAb (R4-6A2) in sterile PBS overnight.…”

“…This was accompanied by an increased frequency of alloreactive T cells as measured by ELIS-POT analysis (38). To address the mechanism by which blockade of PD:PD-L pathway accelerates rejection, we first measured the frequency of IFN-␥-producing donor-specific T cells in untreated recipients and recipients treated with blocking Abs, using a previously published ELISPOT assay (37)(38)(39). Recipient splenocytes were collected 14 days after transplantation, and the frequency of IFN-␥-producing allospecific cells was measured.…”

Sensitization after Kidney Transplantation

“…Blocking these pathways was shown to decrease antidonor antibody responses in animal models (61)(62)(63). The potential beneficial effect of blocking co-stimulation pathways on the development of de novo anti-HLA antibodies in clinical transplantation will require further studies.…”

ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4+ T cells

“…For instance, ICOS-deficient mice display resistance to collageninduced arthritis [23]. Moreover, in vivo blockade of the ICOS/B7h interaction increases allograft survival or accelerates rejection in different experimental settings [24,25]. ICOS function in CD8 + cells is less known.…”