Immune Exhaustion and Transplantation

Abstract

Exhaustion of lymphocyte function through chronic exposure to a high load of foreign antigen is well established for chronic viral infection and antitumor immunity and has been found to be associated with a distinct molecular program and characteristic cell surface phenotype. Although exhaustion has most commonly been studied in the context of CD8 viral responses, recent studies indicate that chronic antigen exposure may affect B cells, NK cells and CD4 T cells in a parallel manner. Limited information is available regarding the extent of lymphocyte exhaustion development in the transplant setting and its impact on anti-graft alloreactivity. By analogy to the persistence of a foreign virus, the large mass of alloantigen presented by an allograft in chronic residence could provide an ideal setting for exhausting donor-reactive T cells. The extent of T cell exhaustion occurring with various allografts, the kinetics of its development, whether exhaustion is influenced positively or negatively by different immunosuppressants, and the impact of exhaustion on graft survival and tolerance development remains a fertile area for investigation. Harnessing or encouraging the natural processes of exhaustion may provide a novel means to promote graft survival and transplantation tolerance.Abbreviations: CTLA4, cytotoxic T lymphocyteassociated protein 4; KLRG1, killer-cell lectin like receptor G1; LCMV, lymphocytic choriomeningitis virus; PD1, programmed cell death 1; PDL1, programmed death ligand 1; TIM3, T cell immunoglobulin domain and mucin domain 3; Treg, regulatory T cell

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…There are several forms of anergy, some of which may be reversed by exogenous IL-2. In contrast, CD8+ T cell exhaustion requires chronic stimulation resulting from an overwhelming antigen load and/or prolonged exposure to an environment that is suboptimal for their response, such as lack of CD4+ T cell help and high level of inhibitory signals [24, 55]. The ability to reverse T cell exhaustion with checkpoint inhibitors has provided a major advance in cancer immunotherapy [54, 56].…”

“…Interestingly, the core transcriptional program of exhausted CD8+ T cells only partly overlaps with that of exhausted CD4+ T cells [57]. T cell exhaustion has been identified as one of the main immune escape mechanisms in the settings of chronic infection and malignancies [24, 55]. The limited studies of exhaustion in clinical transplantation include studies in HCV-infected liver transplant recipients [55].…”

“…T cell exhaustion has been identified as one of the main immune escape mechanisms in the settings of chronic infection and malignancies [24, 55]. The limited studies of exhaustion in clinical transplantation include studies in HCV-infected liver transplant recipients [55]. Chronic exposure to alloantigens and the blunting of the immune response by immunotherapies provides the conditions that promote T cell exhaustion, which is therefore likely to be a mechanism involved in other tolerance settings [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].…”

Regulatory T cell therapy: An option to induce operational tolerance in liver transplantation

“…By contrast, OT takes place only after several years [7]. OT may rely on Treg, but also probably on B cells, NK/NKT cells, myeloid-derived suppressor cells and tolerogenic dendritic cells [15][16][17][18]. OT is not a definitive status, and rejection may occur after years [3,7].…”