Memory T cells play a key role in allograft rejection. They represent a sizeable proportion of the alloreactive T cell repertoire and are superior to naive T cells in driving the effector mechanisms of acute and chronic rejection. Much of the research on immune memory in transplantation has focused on circulating effector (TEM) and central (TCM) memory T cells. Recent studies have identified large populations of non- circulating, resident memory T cells (TRM) that provide local immunity in non-lymphoid tissues and are phenotypically, transcriptionally, and functionally distinct from TEM and TCM. TRM- phenotype cells have been identified in human small bowel and lung allografts but their biology and function in transplantation are poorly understood. During the past funding period, we established a mouse kidney transplantation model in which allografts undergo slow, chronic rejection, and monoclonal and polyclonal T cells that infiltrate the graft can be tracked and interrogated over time. Using this model, we could show that TRM (defined by their phenotype, transcriptional profile, non-circulatory behavior, and function) form in the graft and contribute to rejection. This led to the central thesis that TRM are maintained locally and sustain rejection locally. In this application we propose to investigate how TRM are maintained in the allograft.
In Aim 1, we will investigate the roles of antigen, dendritic cells, and the cytokine IL-15.
In Aim 2, we will investigate the role of a specific transcriptional and post-transcriptional regulator (Ebp1), identified by single cell transcriptional analysis, that enhances cell proliferation and survival. In both aims we will study the effects of interrupting TRM maintenance on chronic rejection. Answering these questions promises to yield novel biological and therapeutic insights applicable to organ transplant rejection and possibly other diseases such as GVHD and autoimmunity.
Despite significant improvement in short-term survival of organ transplants, attrition of transplanted organs over time due to chronic rejection remains a significant clinical problem. Identifying the mechanisms by which memory T lymphocytes, a key cell of the immune system, can persist in transplanted organs and cause damage could lead to novel therapies that enhance long-term graft and patient survival.
| Hughes, Andrew D; Lakkis, Fadi G; Oberbarnscheidt, Martin H (2018) Four-Dimensional Imaging of T Cells in Kidney Transplant Rejection. J Am Soc Nephrol 29:1596-1600 |
| Dai, Hehua; Friday, Andrew J; Abou-Daya, Khodor I et al. (2017) Donor SIRP? polymorphism modulates the innate immune response to allogeneic grafts. Sci Immunol 2: |
| Zhang, Qianqian; Dai, Hehua; Yatim, Karim M et al. (2016) CD8+ Effector T Cell Migration to Pancreatic Islet Grafts Is Dependent on Cognate Antigen Presentation by Donor Graft Cells. J Immunol 197:1471-6 |
| Zhuang, Quan; Liu, Quan; Divito, Sherrie J et al. (2016) Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. Nat Commun 7:12623 |
| Tieu, Roger; Lakkis, Fadi G; Oberbarnscheidt, Martin H (2016) Getting Down and Dirty: Germ-Exposed Laboratory Mice as a Model of the Adult Human Immune System. Transplantation 100:2490-2491 |
| Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843 |
| Yatim, Karim M; Lakkis, Fadi G (2015) A brief journey through the immune system. Clin J Am Soc Nephrol 10:1274-81 |
| Zhuang, Quan; Lakkis, Fadi G (2015) Dendritic cells and innate immunity in kidney transplantation. Kidney Int 87:712-8 |
| Walch, Jeffrey M; Lakkis, Fadi G (2014) T-cell migration to vascularized organ allografts. Curr Opin Organ Transplant 19:28-32 |
| Walch, Jeffrey M; Zeng, Qiang; Li, Qi et al. (2013) Cognate antigen directs CD8+ T cell migration to vascularized transplants. J Clin Invest 123:2663-71 |
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