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 8

Endogenous memory CD8+ T cell proliferation within allografts subjected to prolonged CIS requires graft p40 but not p35.

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Endogenous memory CD8+ T cell proliferation within allografts subjected ...
(A) Groups of A/J mice (n = 4–8/group) received cardiac allografts subjected to 0.5 or 8 hours of CIS from either WT C57BL/6 (WTB6) or B6.IL12p40–/– donors. The indicated recipients of WT allografts were treated with 200 μg anti–IL-12 p40 mAb i.p. on days 0 and 1. All recipients were injected with 100 μg BrdU i.p. on days 0 and 1 after transplant. The following day, allografts were harvested and digested, and cell aliquots were stained with antibody and analyzed by flow cytometry to assess total numbers and proliferation of infiltrating memory CD4+ and CD8+ T cells. *P < 0.05; **P < 0.01, as determined by the Mann-Whitney nonparametric test. (B) Groups of A/J mice (n = 4/group) received cardiac allografts subjected to 0.5 or 8 hours of CIS from WT C57BL/6 or B6.IL12p35–/– donors. All recipients were injected with 100 μg BrdU i.p. on days 0 and 1. On day 2 after transplant, allografts were harvested and digested, and cell aliquots were stained with antibody and analyzed by flow cytometry to assess total numbers and proliferation of infiltrating memory CD4+ and CD8+ T cells. *P < 0.05 as determined by the Mann-Whitney nonparametric test. (C) Groups of C57BL/6 mice (n = 5–6/group) received C57BL/6 cardiac isografts or A/J cardiac allografts subjected to 0.5 or 8 hours of CIS. Grafts were harvested on day 2 after transplant, total RNA was isolated, and expression of the indicated cytokine mRNA was tested by qPCR. Results shown indicate relative expression vs. expression in naive hearts of A/J mice. **P < 0.01, as determined by the Mann-Whitney nonparametric test.