Lung allograft acceptance

One of the major challenges in solid organ tissue transplantation is long-term survival of the allograft. The development of memory CD8+ T cell responses in recipients has been associated with rejection of transplanted organs, and protocols that target memory T cell populations are currently being explored in pre-clinical models. Using a murine model of lung allograft acceptance, Alexander Krupnick and colleagues identified a surprising link between allograft survival and infiltration of central memory CD8+ T cells into the transplanted tissue. Two-photon intravital microscopy revealed that T cell expression of the chemokine CCR7 was required for stable interactions with antigen presenting cells. These interactions resulted in IFNγ and NO production, thereby dampening the immune response. In a companion commentary, Xinguo Jiang and Mark Nicolls discuss how these findings impact our understanding of the mechanisms underlying lung allograft acceptance.The accompanying intravital two-photon microscopy (iTPM) image of the lungs of a live mouse 4 days after transplantation shows that WT CD8+ T cells (blue) have drastically increased retention times with CD11c+ anitgen presenting cells (green) compared to T cells lacking CCR7 (red).  Circled cells illustrate the three-dimensional aspects of iTPM.

Published February 25, 2014, by Corinne Williams

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Central memory CD8+ T lymphocytes mediate lung allograft acceptance
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
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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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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Working toward immune tolerance in lung transplantation
Xinguo Jiang, Mark R. Nicolls
Xinguo Jiang, Mark R. Nicolls
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Commentary

Working toward immune tolerance in lung transplantation

Abstract

Long-term allograft survival is a major challenge facing solid organ transplantation. Recent studies have shown a negative correlation between infiltration of memory T cells and allograft survival. Furthermore, blockade of leukocyte activation increases acceptance of transplanted organs, including heart, liver, and kidney. Lung allografts are associated with high rates of rejection, and therapies that increase acceptance of other transplanted organs have not translated into the lung. In this issue of the JCI, Krupnick and colleagues demonstrate in a murine model that lung allograft acceptance requires infiltration of a specific T cell population into the graft. This study highlights the unique immunobiology of the lung and the complexity of lung transplant tolerance.

Authors

Xinguo Jiang, Mark R. Nicolls

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