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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Figure 5

IFN-γ–producing central memory CD8+CD44hiCD62LhiCCR7+ T cells infiltrate accepting lung allografts.

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IFN-γ–producing central memory CD8+CD44hiCD62LhiCCR7+ T cells infiltrate...
(A) Flow cytometry of CD8+ T lymphocytes in lung allografts of acceptors demonstrated few Foxp3+– or IL-10–producing cells. A large proportion of lung-resident CD8+ T cells had the capacity to produce IFN-γ and expressed a central memory phenotype (CD44hiCD62LhiCCR7+). (B) Fewer cells in spleens of lung graft recipients had the capacity to produce IFN-γ, and only few cells had a central memory T cell phenotype. Numbers in density plots in A and B represent percentages of CD8+ T cells expressing indicated markers. Phenotype of CD8+ T cells is representative of at least 4 separate experiments.