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T-bet or IFNγ Neutralization for Blocking Islet Allograft Rejection?

Le Moine, Alain, MD, PhD1

doi: 10.1097/TP.0000000000002262
Commentaries

A commentary discussing the potential implications of the findings that T-bet deficiency abrogates the ability to acutely reject allogeneic islet allografts whereas IFNγ-deficiency does not.

1 Nephrology-Dialysis-Transplantation Department, Erasme Hospital, Institute for Medical Immuology (IMI), Université libre de Bruxelles, Brussels, Belgium.

Received 7 April 2018. Revision received 23 April 2018.

Accepted 24 April 2018.

The author declares no conflicts of interest.

Correspondence: Alain Le Moine, MD, PhD, Nephrology-Dialysis-Transplantation Department, Erasme Hospital, Institute for Medical Immuology (IMI), Université libre de Bruxelles, Brussels, Belgium. (alemoine@ulb.ac.be; Alain.Lemoine@erasme.ulb.ac.be).

In this issue, Besançon and colleagues1 report that although IFNγ−/− recipient mice reject fully allogeneic islet allografts, whereas T-bet−/− recipients do not. T-bet is considered the master regulator for T-helper 1 (Th1) type immune responses where Th1-differentiated cells release large amounts of IFNγ and CD8+ T cells acquire cytolytic activity. Nevertheless, the respective roles played by IFNγ or T-bet in rejection processes remain complex, and the work by Besançon et al brings new insights. Indeed, they unravel compensatory mechanisms leading to Th1 graft rejection in IFNγ−/− recipients and those that are definitely dampened in T-bet−/− recipients. In addition, they provide arguments suggesting a protective (antirejection) effect played by IFNγ. Because they rely on a basic immunology approach, compelling evidence suggests that they may be extrapolated to other transplant settings, even though islets are nonvascularized transplants.

In a historical perspective, observations reporting a causal relationship between IFNγ and allograft rejection were actually scarce and very often model-dependent (reviewed in Le Moine et al2). Most of the time, neutralization of IFNγ or IL-12 (an upstream pro-Th1 cytokine mainly produced by antigen presenting cells) biased T-cell responses toward other T-helper pathways, such as Th2 or Th17, but did not abrogate allograft rejection.2-5 This has been interpreted as the consequence of a crisscross regulation between the different T-helper cell subtypes during their differentiation process (Figure 1) or the persistence of alloreactive cytotoxic CD8+ T cells. Later on, several models using T-bet−/− recipient mice have highlighted the effector role of either CD4+ Th17 cells or CD8+ “Th17” cells in heterotopic cardiac allograft rejection.6-8 In the latter, CD8+ Th17 cells mediated CD40-CD40 ligand costimulation blockade-resistant rejection.8 Notably, the previously reported T-bet dispensability for cardiac allograft rejection raises the question about a possible dedicated CD4+ and/or CD8+ “Th17” pathway for vascularized allografts. Those pioneering works already challenged the dogma of an essential role of IFNγ in allograft rejection.

FIGURE 1

FIGURE 1

Because of a possible crisscross regulation between T-helper cells, Besançon and colleagues ruled out alternative Th17 or Th2 pathways of allograft rejection in IFNγ−/− recipients. Similarly, there was no support for a theoretically protective Th2-mediated (IL-4–producing) immune response in T-bet−/− recipients, but rather a decreased intragraft CD4+ and CD8+ T-cell infiltrates compared with wild type or IFNγ−/− recipients. This was explained by a decreased T-cell proliferation and an enhanced susceptibility of T-bet−/− CD8+ (but not CD4+) activated T cells to cell death as attested by T cell count and markers of apoptosis (Fas, Annexin V, and caspase-3 expression). In addition, cytolytic program was dampened in T-bet−/− mice (perforin 1, granzyme B, Fas-ligand), whereas the opposite feature was noticed in IFNγ−/− recipients. The latter point was explained by a compensatory higher expression of the transcription factor eomesodermin (Eomes). Normally, Eomes cooperates with T-bet in Th1 differentiation, IFNγ production, T-cell cytotoxicity, and central memory CD8+ T-cell responses (discussed in the article). Interestingly, a double deficiency of T-bet and ROR-γ (a Th17 transcription factor) has been reported to induce a rapid Th-2–mediated cardiac allograft rejection with eosinophil infiltrate.7 In this setting, IL-4 neutralization (an essential Th2 growth factor) abolished rejection in half of the recipients and upregulated Eomes and IFNγ in rejecting animals. This provides an additional setting in which a Th1, Th2, and Th17 combined inhibition leads to Eomes and IFNγ upregulation and allograft rejection.

Finally, the authors underline the fact that IFNγ is known to induce the expression of programmed death-ligand 1 (PD-L1) on T cells and antigen-presenting cells, which was confirmed by a decreased expression of PD-L1 on T cells in IFNγ−/− allograft recipients. The PD-1/PD-L1 pathway is considered a master regulator in many immune responses, including alloreactivity, autoimmunity, and antitumor immunity. Blocking this pathway has been shown to be promising for cancer treatment (the checkpoint inhibitor approach) but induces dysimmunity.9 The possible causal relationship between the rejection by IFNγ−/− recipient and an enhancer role played by the reduced expression of PDL-1 observed on T cells (but not in wild type or Tbet−/−) is an exciting hypothesis but remains to be proved. Remarkably, long time ago, IFNγ production has been identified as a necessary condition for transplantation tolerance induction after costimulation blockade.10

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