Recipient Myd88 deficiency promotes spontaneous resolution of kidney allograft rejection

Nadine M. Lerret, Ting Li, Jiao Jing Wang, Hee Kap Kang, Sheng Wang, Xueqiong Wang, Chunfa Jie, Yashpal S. Kanwar, Michael M. Abecassis, Xunrong Luo, Zheng Zhang

Research output: Contribution to journalArticle

Abstract

The myeloid differentiation protein 88 (MyD88) adapter protein is an important mediator of kidney allograft rejection, yet the precise role ofMyD88 signaling in directing the host immuneresponse toward thedevelopment of kidney allograft rejection remains unclear.Using a stringent mousemodel of allogeneic kidney transplantation, we demonstrated that acute allograft rejection occurred equally in MyD88-sufficient (wild-type [WT]) and MyD882/2recipients. However,MyD88deficiency resulted inspontaneous diminution of graft infiltratingeffector cells, including CD11b2Gr-1+ cells and activated CD8 T cells, as well as subsequent restoration of near-normal renal graft function, leading to long-term kidney allograft acceptance. Compared with T cells fromWTrecipients, T cells fromMyD882/2 recipients failed to mount a robust recall response upon donor antigen restimulation in mixed lymphocyte cultures ex vivo. Notably, exogenous IL-6 restored the proliferation rate of T cells, particularly CD8 T cells, from MyD882/2 recipients to the proliferation rate of cells from WT recipients. Furthermore, MyD882/2 T cells exhibited diminished expression of chemokine receptors, specifically CCR4 and CXCR3, and the impaired ability to accumulate in the kidney allografts despite an otherwise MyD88-sufficient environment. These results provide a mechanism linking the lack of intrinsic MyD88 signaling in T cells to the effective control of the rejection response that results in spontaneous resolution of acute rejection and long-term graft protection.

Original languageEnglish (US)
Pages (from-to)2753-2764
Number of pages12
JournalJournal of the American Society of Nephrology
Volume26
Issue number11
DOIs
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Lerret, N. M., Li, T., Wang, J. J., Kang, H. K., Wang, S., Wang, X., Jie, C., Kanwar, Y. S., Abecassis, M. M., Luo, X., & Zhang, Z. (2015). Recipient Myd88 deficiency promotes spontaneous resolution of kidney allograft rejection. Journal of the American Society of Nephrology, 26(11), 2753-2764. https://doi.org/10.1681/ASN.2014080813