Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells
Hidetoshi Tsuda, Charles A. Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, Robert L. Fairchild
Hidetoshi Tsuda, Charles A. Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, Robert L. Fairchild
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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 7

Elevated expression of IL12p40 mRNA in allografts subjected to 8 hours of CIS.

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Elevated expression of IL12p40 mRNA in allografts subjected to 8 hours o...
(A) Groups of C57BL/6 (n = 4–6/group) mice received C57BL/6 isografts subjected to 8 hours of CIS or A/J cardiac allografts subjected to either 0.5 or 8 hours of CIS. The indicated recipients of 8-hour CIS allografts were treated with 200 μg control rat IgG or anti-CD4 mAb on days –3, –2, and –1 prior to transplant. They then received A/J cardiac allografts subjected to 8 hours of CIS and then either 100 μg control rat IgG or agonist anti-CD40 mAb i.v. on days 0 and 1 after transplant. Grafts were harvested on day 2 after transplant, total RNA was isolated, and expression of the indicated cytokine mRNAs was 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. (B) For the indicated groups of C57BL/6 (n = 5/group) allograft recipients in A, 100 μg BrdU was given i.p. on days 0 and 1 after transplant. The next day, all allografts were harvested and digested, and aliquots of single cells were stained with antibody and analyzed by flow cytometry to assess infiltrating memory CD8+ T cell proliferation and their expression of IL-12R β1 and IL-12R β2. *P < 0.05, **P < 0.01, as determined by the Mann-Whitney nonparametric test.