TGFβ-dependent expression of PD-1 and PD-L1 controls CD8+ T cell anergy in transplant tolerance

Abstract

CD8+ T cell anergy is a critical mechanism of peripheral tolerance, poorly investigated in response to immunotherapy. Here, using a pancreatic islet allograft model and CD3 antibody therapy, we showed, by single cell gene profiling, that intragraft CD8+ lymphocytes coexpressing granzyme B and perforin were selectively depleted through the Fas/FasL pathway. This step led to long-standing anergy of the remaining CD8+ T cells marked by the absence of cytotoxic/inflammatory gene expression also confirmed by transcriptome analysis. This sustained unresponsiveness required the presence of the alloantigens. Furthermore, tissue-resident CD8+ lymphocytes produced TGFβ and expressed the inhibitory receptors PD-1 and PD-L1. Blockade of TGFβ downregulated PD-1 and PD-L1 expression and precipitated graft rejection. Neutralizing PD-1, PD-L1 or TGFβRII signaling in T cells also abrogated CD3 antibody-induced tolerance. These studies unravel novel mechanisms underlying CD8+ T cell anergy and reveal a cell intrinsic regulatory link between the TGFβ and the PD-1/PD-L1 pathways.DOI: http://dx.doi.org/10.7554/eLife.08133.001

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…Reduced expression of the AP-1 complex was also noticed in tolerant T cells infiltrating islet allografts after anti-CD3 antibody [62]. Moreover, CD8+ T cells isolated from tolerated islet allografts failed to produce IFNγ in response to donor antigens [62].…”

“…Moreover, CD8+ T cells isolated from tolerated islet allografts failed to produce IFNγ in response to donor antigens [62]. Single cell PCR of individual graft-infiltrating CD8+ T cells revealed high expression of the inhibitory receptors LAG-3, TGF-β-induced PD-1, PDL-1, as well as increased expression of Eomes in tolerant compared to control CD8+ T cells [62], highly suggestive of T cell exhaustion [55].…”

“…Moreover, CD8+ T cells isolated from tolerated islet allografts failed to produce IFNγ in response to donor antigens [62]. Single cell PCR of individual graft-infiltrating CD8+ T cells revealed high expression of the inhibitory receptors LAG-3, TGF-β-induced PD-1, PDL-1, as well as increased expression of Eomes in tolerant compared to control CD8+ T cells [62], highly suggestive of T cell exhaustion [55]. Furthermore, downregulated expression of hypoxia-inducible factor HIFα in tolerant CD8+ T cells [62] is aligned with the low metabolic requirement and the high expression of VHL in exhausted T cells [63].…”

PD-L1 serves as a double agent in separating GVL from GVHD

“…As Ni and colleagues only showed an increase in systemic IFN-γ levels in the absence of CD4 + T cells, it would be important to delineate whether IFN-γ expression is also increased within the local environment. Similarly, in addition to IFN-γ, other cytokines, such as IL-27 and TGF-β, can upregulate expression of PD-L1 (25,26). Although Ni et al found no notable differences in serum IL-27 concentrations in recipients treated with anti-CD4 mAb compared with a finding using multiple GVHD models (two murine allogeneic HCT models and a human → mouse xenogeneic HCT model) and two tumor models, including one that was previously shown to be partially resistant to the GVL effect (23).…”

Immunoregulatory functions of PD-1/PD-L1 inhibitors and development of resistance to them

“…Повышенное значение VEGF, TGF и IL10 в опухолевом микроокружении так-же способствует развитию резистентности к анти-PD1 терапии, предотвращая активацию опухоль-специфи-ческих Т-лимфоцитов [44,45,46]. Более того, на ксе-нографтах мышей было продемонстрировано, что TGF модулирует экспрессию PD-1 и PD-L1 [47]. Ко-экспрес-сия других ингибиторных рецепторов в дополнение к PD-1, таких, как TIM3 (T-cell immunoglobulin mucin 3), LAG3 (lymphocyte activation gene 3), CTLA4 и BTLA (B and T lymphocyte attenuator), ассоциируется с раз-витием резистентности к анти-PD1 терапии, что было продемонстрировано при немелкоклеточном раке лег-кого [48].…”