Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival

The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed...

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Autores principales:	Romy Steiner, Anna M. Weijler, Thomas Wekerle, Jonathan Sprent, Nina Pilat
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	transplantation allo-recognition Regulatory T cells (Tregs) tolerance IL-2 complexes passenger leucocytes Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/68eb7f9e7dcd428b85c5b90a689eb8c0
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spelling	oai:doaj.org-article:68eb7f9e7dcd428b85c5b90a689eb8c02021-12-01T11:06:08ZImpact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival1664-322410.3389/fimmu.2021.801595https://doaj.org/article/68eb7f9e7dcd428b85c5b90a689eb8c02021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.801595/fullhttps://doaj.org/toc/1664-3224The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient’s immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.Romy SteinerAnna M. WeijlerThomas WekerleJonathan SprentJonathan SprentNina PilatNina PilatFrontiers Media S.A.articletransplantationallo-recognitionRegulatory T cells (Tregs)toleranceIL-2 complexespassenger leucocytesImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	transplantation allo-recognition Regulatory T cells (Tregs) tolerance IL-2 complexes passenger leucocytes Immunologic diseases. Allergy RC581-607
spellingShingle	transplantation allo-recognition Regulatory T cells (Tregs) tolerance IL-2 complexes passenger leucocytes Immunologic diseases. Allergy RC581-607 Romy Steiner Anna M. Weijler Thomas Wekerle Jonathan Sprent Jonathan Sprent Nina Pilat Nina Pilat Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival
description	The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient’s immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.
format	article
author	Romy Steiner Anna M. Weijler Thomas Wekerle Jonathan Sprent Jonathan Sprent Nina Pilat Nina Pilat
author_facet	Romy Steiner Anna M. Weijler Thomas Wekerle Jonathan Sprent Jonathan Sprent Nina Pilat Nina Pilat
author_sort	Romy Steiner
title	Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival
title_short	Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival
title_full	Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival
title_fullStr	Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival
title_full_unstemmed	Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival
title_sort	impact of graft-resident leucocytes on treg mediated skin graft survival
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/68eb7f9e7dcd428b85c5b90a689eb8c0
work_keys_str_mv	AT romysteiner impactofgraftresidentleucocytesontregmediatedskingraftsurvival AT annamweijler impactofgraftresidentleucocytesontregmediatedskingraftsurvival AT thomaswekerle impactofgraftresidentleucocytesontregmediatedskingraftsurvival AT jonathansprent impactofgraftresidentleucocytesontregmediatedskingraftsurvival AT jonathansprent impactofgraftresidentleucocytesontregmediatedskingraftsurvival AT ninapilat impactofgraftresidentleucocytesontregmediatedskingraftsurvival AT ninapilat impactofgraftresidentleucocytesontregmediatedskingraftsurvival
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Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival

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