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.
View: Text | PDF
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

×

Figure 2

Anti-CD122 mAb but not anti-CD25 mAb inhibits endogenous memory CD8+ T cell proliferation within highly ischemic allografts.

Options: View larger image (or click on image) Download as PowerPoint
Anti-CD122 mAb but not anti-CD25 mAb inhibits endogenous memory CD8+ T c...
(A) C57BL/6 (n = 5–6 per group) mice received A/J cardiac allografts subjected to 0.5 or 8 hours of CIS. Recipients of 8-hour-CIS allografts were treated with 200 μg control rat IgG or anti-CD4 mAb on days –3, –2, and –1 before transplant. Grafts were harvested on day 2, infiltrating CD8+ T cells were enriched by negative selection, and total RNA was isolated and tested for expression of the indicated cytokine receptor mRNAs by quantitative PCR. Results shown indicate relative expression by infiltrating CD8+ T cells versus expression in purified splenic CD8+ T cells from naive A/J mice. *P < 0.05 as determined by Kruskal-Wallis test. (B) C57BL/6 mice (n = 5–7 per group) received A/J cardiac allografts subjected to 8 hours of CIS and were treated with 100 μg BrdU and either 100 μg control rat IgG, anti-CD25 mAb, or anti-CD122 mAb i.p. on days 0 and 1. On day 2, allografts were harvested and digested, and cell suspensions were stained with antibody and analyzed by flow cytometry to assess total numbers and proliferation of infiltrating memory CD4+ and CD8+ T cells. **P < 0.01 as determined by the Kruskal-Wallis test. (C) C57BL/6 mice (n = 5 per group) received A/J cardiac allografts subjected to 0.5 hours of CIS. The indicated recipients were treated with 100 μg BrdU and 200 μg control rat IgG or anti-CD122 mAb i.p. on days 0 and 1 and with 2 μg recombinant p40HDs i.v. on day 1. On day 2, allografts were harvested and digested, and cell suspensions were stained with antibody and analyzed by flow cytometry to assess total numbers and proliferation of infiltrating memory CD8+ T cells. *P < 0.05 as determined by Mann-Whitney nonparametric test.