Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells
Hidetoshi Tsuda, … , Anna Valujskikh, Robert L. Fairchild
Hidetoshi Tsuda, … , Anna Valujskikh, Robert L. Fairchild
Published February 22, 2018
Citation Information: JCI Insight. 2018;3(4):e96940. https://doi.org/10.1172/jci.insight.96940.
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Research Article Immunology Transplantation

Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

Abstract

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade–induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4+ and CD8+ T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8+ T cells directly mediate CTLA-4Ig–resistant allograft rejection. Memory CD8+ T cell activation within allografts subjected to prolonged CIS requires memory CD4+ T cell stimulation of graft DCs to produce p40 homodimers, but not IL-12 p40/p35 heterodimers. Targeting p40 abrogates memory CD8+ T cell proliferation within the allografts and their ability to mediate CTLA-4Ig–resistant allograft rejection. These findings indicate a critical role for memory CD4+ T cell–graft DC interactions to increase the intensity of endogenous memory CD8+ T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS.

Authors

Hidetoshi Tsuda, Charles A. Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, Robert L. Fairchild

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Figure 6

Endogenous memory CD8+ T cell proliferation in allografts subjected to prolonged CIS requires graft DCs.

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Endogenous memory CD8+ T cell proliferation in allografts subjected to p...
(A) Groups of A/J mice (n = 5/group) received cardiac allografts subjected to 8 hours of CIS from B6.DTR-CD11c transgenic mice that had been treated with or without diphtheria toxin (DT; 4 ng/g body weight) on days –2 and –1 prior to transplantation. On days 0 and 1 after transplant, all recipients were injected with 100 μg BrdU i.p. The following day, allografts were harvested and digested, and aliquots of single cell suspensions were stained with antibody and analyzed by flow cytometry to quantitate the infiltration and proliferation of memory CD4+ and CD8+ T cells. *P < 0.05, as determined by the Mann-Whitney nonparametric test. (B) Groups of A/J mice (n = 4–6/group) received cardiac isografts or allografts subjected to either 0.5 or 8 hours of CIS from WT C57BL/6 mice or B6.DTR-CD11c transgenic mice treated with DT prior to harvest and transplant. On day 2 after transplant, RNA was isolated from harvested grafts and expression of the indicated cytokines tested by qPCR. Results shown indicate relative expression vs. expression in naive hearts of C57BL/6 mice. *P < 0.05, as determined by the Mann-Whitney nonparametric test. (C) Groups of A/J mice (n = 5/group) received cardiac allografts subjected to 8 hours of CIS from B6.DTR-CD11c transgenic mice treated with or without DT on days –2 and –1 prior to transplantation. On day 8 after transplant, recipient spleen cells were tested to determine numbers of donor-reactive T cells producing IFN-γ or IL-17 by ELISPOT assay. *P < 0.05, as determined by the Mann-Whitney nonparametric test.