A Novel Alloantigen-Specific CD8+PD1+ Regulatory T Cell Induced by ICOS-B7h Blockade In Vivo

Abstract

Delayed ICOS-B7h signal blockade promotes significant prolongation of cardiac allograft survival in wild-type but not in CD8-deficient C57BL/6 recipients of fully MHC-mismatched BALB/c heart allografts, suggesting the possible generation of CD8+ regulatory T cells in vivo. We now show that the administration of a blocking anti-ICOS mAb results in the generation of regulatory CD8+ T cells. These cells can transfer protection and prolong the survival of donor-specific BALB/c, but not third party C3H, heart grafts in CD8-deficient C57BL/6 recipients. This is unique to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice and does not result in the generation of regulatory CD8+ T cells. Those cells localize to the graft, produce both IFN-γ and IL-4 after allostimulation in vitro, prohibit the expansion of alloreactive CD4+ T cells, and appear to mediate a Th2 switch of recipient CD4+ T cells after adoptive transfer in vivo. Finally, these cells are not confined to the CD28-negative population but express programmed death 1, a molecule required for their regulatory function in vivo. CD8+PD1+ T cells suppress alloreactive CD4+ T cells but do not inhibit the functions by alloreactive CD8+ T cells in vitro. These results describe a novel allospecific regulatory CD8+PD1+ T cell induced by ICOS-B7h blockade in vivo.

Mechanism and Localization of CD8 Regulatory T Cells in a Heart Transplant Model of Tolerance

“…+ Tregs have been shown to play a central role in vivo in donor-specific blood transfusion-induced tolerance (3) and anti-ICOS-treated mice (4). Furthermore, we have shown in rats that blockade of CD40-CD40L interactions with CD40Ig-induced tolerogenic CD8 + CD45RC low Tregs, which generated infectious tolerance upon adoptive transfer (5).…”

“…Contact with pDCs was necessary to trigger suppression by tolerogenic CD8 + Tregs in our model. Although CTLA4 (33,34) or the programmed death-1 (PD-1) ligand (4) in coculture MLR. Fgl-2 is a membrane and/or secreted molecule induced by IFN-g and produced by CD4 + CD25 + Tregs (38) and TCR + CD8 + aa intraepithelial lymphocytes (39).…”

Impaired CD4 and CD8 Effector Function and Decreased Memory T Cell Populations in ICOS-Deficient Patients

“…4, C and D). The percentages of PD1 ϩ CD8 T cells, which function as inhibitory T cells (43), were slightly reduced only in patient 2 (29.0%) compared with controls (49.8 Ϯ 9.0%, n ϭ 7).…”

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

“…58 In a cardiac allograft mouse model, ICOS blockade induced a novel antigenspecific CD8 ϩ PD1 ϩ regulatory T-cell population. 59 Collectively, these results suggest that the ICOS-ICOSL costimulatory pathway is complex and its blockade leads to different effects depending on the immunologic challenge, timing of the blockade, and/or disease model. 60 In our model, anti-ICOS mAb treatment during the early phase of gene therapy effectively eliminated FVIII specific effector T cells in the spleen, LNs, and PBMCs of hFVIII plasmid-treated mice.…”