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Research Highlights

Muller, Elmi, MBChB, MMED1

doi: 10.1097/TP.0000000000002131
In View: Research Highlights

1 Department of Surgery, Groote Schuur Hospital, University of Cape Town, Observatory Cape Town, Western Cape, South Africa.

Received 6 February 2018. Revision received 8 February 2018.

Accepted 9 February 2018.

The author declares no conflicts of interest.

Correspondence: Elmi Muller, MBChB, MMED, Groote Schuur Hospital, Main Road, Observatory Cape Town, Western Cape 7925, South Africa. (elmi.muller@uct.ac.za).

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Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction

Jie Wu, Hedong Zhang, Xiamomin Shi, et al. Immunity. 2017;47(6):1114–1128.e6.

The transcriptional programs regulating allogenic T-cell responses have not been adequately documented thus far. Here, the authors used a knockout mouse model to demonstrate the importance of interferon regulatory factor 4 (IRF4) in controlling graft rejection. IRF4 is a key transcriptional factor running T-cell responses during and after transplantation.

The authors performed several experiments on IRF4 deficient (IRF4−/−) as well as wild type mice by transplanting them with mismatched heart allografts. First, they demonstrated that graft-infiltrating T cells expressed a consistently elevated mean fluorescence intensity of IRF4. Notably, they were able to show that IRF4−/− mice did not reject their allografts. Moreover, all IRF−/− mice survived the observation period of 100 days with intact myocytes and only minimal cellular infiltrates into the graft. The authors then went on transferring either 2 million wild type CD4+ or CD8+ T cells or 20 million IRF4−/− CD4+ or CD8+ T cells into IRF4−/− mice and found that the adaptive transfer of unmanipulated T cells facilitated rejection, whereas the transfer of IRF−/− T cells did not. Furthermore, IRF4−/− mice failed to show increased T cells in their spleen after transplantation, indicating that expansion of alloreactive T cells in IRF4−/− was impaired. Mechanistically, the authors demonstrated the critical role of PD-1 expression by alloantigen-specific T cells for the long-term acceptance of cardiac allografts in IRF−/− mice.

Finally, the authors showed that trametinib, a MEK1/2 inhibitor most potently reduced IRF4 expression in activated T cells, inhibited Th1 and Th17 cell differentiation and prolonged heart allograft survival.

This intriguing data show the critical role of IRF4 expression on T cells in alloimmunity and indicate the translational potential of trametinib to in improving transplant outcomes.

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Cutting Edge: Allograft Rejection Is Associated With Weak T-Cell Responses to Many Different Graft Leukocyte-Derived Peptides

Burrack AL, Malhotra D, Dileepan T, Osum KC, Swanson LA, Fife BT, Jenkins MK. J Immunol. 2018; 200: 477–482.

Allografts are rejected by T lymphocytes that recognize foreign MHC class I and II antigens. The robustness of this T-cell response, however, is not understood. Previous concepts have attributed the rejection process largely on the frequency of T cells that recognize either allogeneic MHC molecules alone or MHC plus-bound peptides.

The authors explored the specificity of directly alloreactive T cells, using a peptide-MHC II tetramer-based approach. Tail skin from H2-DM- and CD74-deficient mice were grafted onto the flanks of recipient laboratory-bred strain house mouse. These grafts were rejected after 10 to 12 days. Spleen, lymph node, or blood cells were harvested and stained 7 to 14 days after transplantation. The total number of tetramer-positive cells in the enriched fraction from each mouse was determined, using AccuCheck counting beads. Differences in T-cell expansion and differentiations after transplantation between and across groups were established. CD4+ cells were identified as viable lymphocyte-sized single cells that expressed CD3 or CD90.2.

Graft-responsive CD4 T cells expanded an average of 28-fold after transplantation. Mice transplanted with B6 skin also demonstrated a clonal T-cell expansion, indicating that this phenomenon was not limited to autoimmunity-prone NOD mice. In the transplanted mice, tetramer binding sites were examined and sites increased fivefold in NOD mice that had been transplanted with B6 skin.

These results demonstrate that directly alloreactive T cells recognize an allogeneic MHC II molecule and a graft leukocyte peptide in the same way that microbe-reactive T cells recognize a syngeneic MHC II molecule and a microbial peptide. The data suggest that the potency of direct alloreactivity is not due to a high frequency of T cells that recognize MHC molecules alone, but rather the consequence of an additional weak activation of T cells, specific for hundreds of different graft leukocyte peptide-allogeneic MHC complexes.

These data have important conceptual relevance in understanding basic mechanisms that drive alloimmunity and inflammation.

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