Endogenous regeneration of the thymus is a crucial function that allows for renewal of immune competence following infection, shock, cytoreductive chemo- or radiation therapy and other causes of thymic injury. Thymic regenerative capacity diminishes with age and remains a poorly understood area. One of the major goals of this project is to elucidate the processes of endogenous thymic regeneration so that they may be exploited into clinically relevant strategies for immune rejuvenation. This is particularly relevan for recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who experience prolonged post-transplant T cell deficiency caused by cytoreductive conditioning and graft-versus-host disease (GVHD), which results in increased morbidity and mortality from infections and malignant relapse. Interleukin-22 (IL-22) is produced by T-helper (Th)17 cells and innate lymphoid cells (ILCs) and promotes innate immunity and homeostasis of epithelial cells in the intestines, lung and skin. We have found a novel role for IL-22 in the endogenous regeneration of thymic epithelial cells (TECs) after thymic damage. We found that IL-22 was redundant for steady-state thymopoiesis but following thymic damage a) absolute levels of IL-22 in the thymus were increased, b) IL-22 production by thymic ILCs (tILCs) was increased, c) IL-23 production by thymic dendritic cells (tDCs) was increased and could enhance IL-22 production by innate lymphoid cells, and d) IL-22 administration could enhance overall thymic cellularity and proliferation and survival of TECs. Our preliminary findings also suggest that IL-22 can affect T cell development as early as bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Based on these findings, we hypothesize that (a) IL-22 plays an important role in endogenous T cell regeneration following thymic insult, (b) IL-22 promotes differentiation and commitment of HSPCs to the lymphoid lineage, and (c) IL- 22 can be utilized as a therapeutic strategy in the clinic to boost thymic function following immune depletion. Our proposal has the following aims: (1) To study the role of IL-22 in endogenous regeneration of thymopoiesis, (2) To study the role of IL-22 in pre-thymic lymphoid commitment and development, and (3) To study the potential for IL-22 administration to improve T cell reconstitution following allo-HSCT. The mechanistic and pre-clinical studies outlined in this proposal have the potential to define an important novel pathway in thymic regeneration, which could result in clinical approaches to enhance T cell immunity, not only for recipients of allo-HSCT, but also for individuals with T cell deficiencies due to aging (lymphoid atrophy), autoimmune diseases, infectious diseases, shock, radio- or chemo-therapy and radiation injury (nuclear accident or terrorism).

Public Health Relevance

Despite being exquisitely sensitive to injury, the thymus (which is fundamental for the development of T cells and the immune system in general) is remarkably resilient in young healthy animals. Understanding the processes involved with this natural regeneration can help us overcome the barriers to repair imposed by age, infection, shock or repeated treatments of chemotherapy or radiation. This proposal aims to further investigate a new framework of natural thymic repair based on a recently identified cytokine, IL-22, and seeks to exploit this process as an innovative clinical strategy for immune regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101406-02
Application #
8477127
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Prabhudas, Mercy R
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$472,513
Indirect Cost
$214,168
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Tuckett, Andrea Z; Thornton, Raymond H; Shono, Yusuke et al. (2014) Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy. Blood 123:2797-805
Geiger, Theresa L; Abt, Michael C; Gasteiger, Georg et al. (2014) Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med 211:1723-31
Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91
Shono, Yusuke; Tuckett, Andrea Z; Ouk, Samedy et al. (2014) A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discov 4:578-91
Ghosh, Arnab; Holland, Amanda M; van den Brink, Marcel R M (2014) Genetically engineered donor T cells to optimize graft-versus-tumor effects across MHC barriers. Immunol Rev 257:226-36
Velardi, Enrico; Dudakov, Jarrod A; van den Brink, Marcel R M (2013) Clinical strategies to enhance thymic recovery after allogeneic hematopoietic stem cell transplantation. Immunol Lett 155:31-5
Ghosh, Arnab; Holland, Amanda M; Dogan, Yildirim et al. (2013) PLZF confers effector functions to donor T cells that preserve graft-versus-tumor effects while attenuating GVHD. Cancer Res 73:4687-96