Central memory CD8+ T lymphocytes mediate lung allograft acceptance
Alexander Sasha Krupnick, … , Andrew E. Gelman, Daniel Kreisel
Alexander Sasha Krupnick, … , Andrew E. Gelman, Daniel Kreisel
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(3):1130-1143. https://doi.org/10.1172/JCI71359.
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Research Article

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

Abstract

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8+ T cells (CD44hiCD62LhiCCR7+). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8+ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8+ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung.

Authors

Alexander Sasha Krupnick, Xue Lin, Wenjun Li, Ryuiji Higashikubo, Bernd H. Zinselmeyer, Hollyce Hartzler, Kelsey Toth, Jon H. Ritter, Mikhail Y. Berezin, Steven T. Wang, Mark J. Miller, Andrew E. Gelman, Daniel Kreisel

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Figure 8

CD8+ T cells suppress through IFN-γ–mediated production of NO.

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CD8+ T cells suppress through IFN-γ–mediated production of NO. (A) Aft...
(A) After 5 days, the majority of CD4+CD45.1+ T cell “responders” are not viable if CD8+ T cells from accepting allografts are added. CD4+CD45.1+ T cell viability (by 7-AAD uptake) and representative plots of CFSE vs. 7-AAD are shown (groups compared by unpaired t test). (B) CD4+ T cell proliferation (CFSE) and viability (7-AAD) in an MLR containing Ifngr1–/– CD4+ T cell responders or Ifngr1–/– antigen-presenting cells (n ≥ 3). Numbers in density plots in A and B represent percentages of CD4+CD45.1+ T cells within the respective quadrants, assessing their proliferation (CFSE) vs. viability (7-AAD). (C) CD4+ T cell proliferation after stimulation with plate-bound anti-CD3 and soluble anti-CD28 in the absence or presence of accepting allograft-derived CD8+ T cells (P = 0.55 between the 2 groups by unpaired t test). (D) CD4+ T cell proliferation with inhibitors of amino acid metabolism, arginine, or Inos–/– antigen-presenting cells (multiple group comparison performed by ANOVA). (E) NO levels in resting lungs, allografts, and right native lungs (n ≥ 3) (unpaired t test). (F) BALB/c lungs transplanted into CSB-treated Inos–/– B6 recipients (P = 0.00059 vs. Figure 2A by Mantel-Haenszel χ2 test). TXP denotes graft, and the arrow points to perivascular infiltrates All gross and histological appearances as well as rejection grades represent grafts at 7 days after transplantation (original magnification, ×200 [histology, H&E staining]).