p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation
Hidetoshi Tsuda, … , Anna Valujskikh, Robert L. Fairchild
Hidetoshi Tsuda, … , Anna Valujskikh, Robert L. Fairchild
Published January 25, 2024
Citation Information: J Clin Invest. 2024;134(6):e172760. https://doi.org/10.1172/JCI172760.
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Research Article

p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation

Abstract

Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses, antigen-reactive naive and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond, whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here, we dissected proliferation of heterologous donor-reactive memory CD8+ T cells and their effector functions following infiltration into heart allografts with low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions required p40 homodimer–induced IL-15 transpresentation by graft DCs, but expression of effector functions mediating acute allograft injury occurred only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8+ T cells were distinct from donor antigen–primed memory CD8+ T cells during early activation in allografts and at graft rejection. Overall, the results provide insights into mechanisms driving heterologous effector memory CD8+ T cell proliferation and the separation between proliferation and effector function that is dependent on the intensity of inflammation within the tissue microenvironment.

Authors

Hidetoshi Tsuda, Karen S. Keslar, William M. Baldwin III, Peter S. Heeger, Anna Valujskikh, Robert L. Fairchild

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Figure 1

p40HD increases IL-15 production within allografts subjected to 30 minutes of CIS prior to transplant.

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p40HD increases IL-15 production within allografts subjected to 30 minut...
(A) A/J cardiac allografts subjected to either 0.5 or 8 hours of CIS were transplanted into C57BL/6 mice. All recipients were injected with 100 μg BrdU i.p. on days 0 and 1 after transplant. On day 2 after transplant, allografts were harvested and digested, and cell suspensions were stained with antibody and analyzed by flow cytometry using the gating strategy shown to assess the proliferation of graft-infiltrating CD8+ T cells in allografts subjected to each of the CIS conditions. (B) Groups of C57BL/6 mice (n = 3–4 per group) received A/J cardiac allografts subjected to 0.5 hours of CIS. The indicated recipients were treated with either 2 μg recombinant p40HDs, recombinant IL-12, or recombinant IL-23 i.v. on day 1 after transplant. All recipients were injected with 100 μg BrdU i.p. on days 0 and 1 after transplant. The next day, allografts were harvested and digested, and cell suspensions were stained with antibody and analyzed by flow cytometry to assess the proliferation of infiltrating CD8+ T cells. *P < 0.05 as determined by the Kruskal-Wallis test. (C and D) Groups of C57BL/6 (n = 4–7 per group) mice received A/J cardiac allografts subjected to 0.5 hours of CIS. The indicated allograft recipients were treated with 2 μg recombinant p40HDs, recombinant IL-12, or recombinant IL-23 i.v. on day 1 after transplant. On day 2 after transplant, grafts were harvested and homogenized, and levels of IL-15 (C) and IL-2 (D) were tested by ELISA. **P < 0.01 vs. 0.5 hours CIS, as determined by the Kruskal-Wallis or the Mann-Whitney nonparametric test.