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T cells, the last samurai against humoral rejection in lung transplants

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Science Translational Medicine  16 Jan 2019:
Vol. 11, Issue 475, eaaw5313
DOI: 10.1126/scitranslmed.aaw5313


Specialized T cells in induced bronchus-associated lymphoid tissue regulate alloimmune responses in the lung allograft.

A major challenge facing clinical organ transplantation is antibody-mediated rejection (AMR) caused by antidonor antibodies. The alloimmune response is highly associated with organ transplant injury, but unfortunately, the rules governing AMR in lung remain enigmatic. There are few efficacious therapies to prevent or reverse AMR. A study by Li et al. identifies a critical role of Foxp3+ T lymphocytes residing within a tertiary lymphoid structure in lung allografts in the regulation of AMR.

In our body, antibodies are made by B cells in strategically placed lymphoid organs. However, lung transplantation, pulmonary infections such as tuberculosis, and lung cancer can result in emerging tertiary lymphoid structures such as induced bronchus-associated lymphoid tissue (iBALT). Li et al. show that Foxp3+ T cells formed aggregates in rejection-free human lung grafts and accumulated within iBALTs of tolerant mouse lungs. The authors show that when allografts from tolerant mice are transplanted into a second recipient, depleting graft-resident Foxp3+ T cells consistently results in AMR. The AMR was a result of the generation of donor-specific antibodies, which was associated with complement deposition and destruction of airway epithelium. Therefore, the regulation of allogeneic humoral responses continues to occur within the lung allograft itself. Since B cell–mediated antibody generation is dependent on T cell help, blockade of C-X-C Motif Chemokine Ligand 13 (CXCL13) or inhibition of ICOS/ICOS ligand and CD40/CD40 ligand pathways suppressed donor-specific antibodies and prevented AMR. The study shows that Foxp3+ T lymphocyte depletion–triggered AMR is dependent on CXCL13-mediated recruitment. These results highlight a potential therapeutic approach against AMR by inhibiting pathways that mediate interactions between T follicular helper cells and B lymphocytes. As pulmonary AMR is largely refractory to current immunosuppression, the findings are an exciting step forward explaining T and B cell interactions at the allograft site. Since the immune responses to lungs are substantially different from those to other transplanted organs, such as kidney and liver, it remains to be explored whether Foxp3+ T lymphocyte serves as the master regulator against humoral rejection in other transplants.

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