Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease

Jarrod A. Dudakov, Anna M Mertelsmann, Margaret H. O’Connor, Robert R Jenq, Enrico Velardi, Lauren F. Young, Odette M Smith, Richard L. Boyd, Marcel R M van den Brink, Alan M Hanash

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22–mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22–dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity post transplant. Manipulation of the ILC–IL-22–TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency.

Original languageEnglish
Pages (from-to)933-942
Number of pages10
JournalBlood
Volume130
Issue number7
DOIs
Publication statusPublished - 17 Aug 2017

Cite this

Dudakov, J. A., Mertelsmann, A. M., O’Connor, M. H., Jenq, R. R., Velardi, E., Young, L. F., ... Hanash, A. M. (2017). Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood, 130(7), 933-942. https://doi.org/10.1182/blood-2017-01-762658
Dudakov, Jarrod A. ; Mertelsmann, Anna M ; O’Connor, Margaret H. ; Jenq, Robert R ; Velardi, Enrico ; Young, Lauren F. ; Smith, Odette M ; Boyd, Richard L. ; van den Brink, Marcel R M ; Hanash, Alan M. / Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. In: Blood. 2017 ; Vol. 130, No. 7. pp. 933-942.
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abstract = "Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22–mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22–dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity post transplant. Manipulation of the ILC–IL-22–TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency.",
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Dudakov, JA, Mertelsmann, AM, O’Connor, MH, Jenq, RR, Velardi, E, Young, LF, Smith, OM, Boyd, RL, van den Brink, MRM & Hanash, AM 2017, 'Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease' Blood, vol. 130, no. 7, pp. 933-942. https://doi.org/10.1182/blood-2017-01-762658

Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. / Dudakov, Jarrod A.; Mertelsmann, Anna M; O’Connor, Margaret H.; Jenq, Robert R; Velardi, Enrico; Young, Lauren F.; Smith, Odette M; Boyd, Richard L.; van den Brink, Marcel R M; Hanash, Alan M.

In: Blood, Vol. 130, No. 7, 17.08.2017, p. 933-942.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Dudakov, Jarrod A.

AU - Mertelsmann, Anna M

AU - O’Connor, Margaret H.

AU - Jenq, Robert R

AU - Velardi, Enrico

AU - Young, Lauren F.

AU - Smith, Odette M

AU - Boyd, Richard L.

AU - van den Brink, Marcel R M

AU - Hanash, Alan M

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AB - Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22–mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22–dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity post transplant. Manipulation of the ILC–IL-22–TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency.

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Dudakov JA, Mertelsmann AM, O’Connor MH, Jenq RR, Velardi E, Young LF et al. Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood. 2017 Aug 17;130(7):933-942. https://doi.org/10.1182/blood-2017-01-762658