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 6

Central memory CD8+ T cells are abundant in the lung and can suppress alloimmune responses both in vitro and in vivo.

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Central memory CD8+ T cells are abundant in the lung and can suppress al...
(A) Compared with other solid organs, such as heart, kidney, and pancreas, the lung contains a relative abundance of CD8+ T lymphocytes, including central memory cells. Central memory (CM) cells are defined as CD44hi62Lhi, effector memory (EM) cells are defined as CD44hi62Llo, and naive cells are defined as CD44lo62Lhi. Data is representative of 4 separate animals. (B) Freshly isolated central memory CD8+ T cells from resting B6 mice suppress proliferation of B6 CD4+CD45.1+ T cells stimulated with BALB/c splenocytes using methodology similar to that described in Figure 4A. Pair-wise comparison between proliferation profiles of responder CD4+CD45.1+ T cells in wells containing no CD8+ T cells, effector memory CD8+ T cells, and central memory CD8+ T cells was performed by unpaired t test. (C) Adoptive transfer of in vitro–generated B6 anti-BALB/c central memory cells into B6 Cd8–/– recipients prevents rejection of BALB/c lung allografts after costimulatory blockade (P = 0.751 compared to Figure 2E by Mantel-Haenszel χ2 test). (D) BALB/c lungs are rejected by B6 Cd8–/– recipient mice reconstituted with in vitro–generated anti-BALB/c CD8+ effector memory T lymphocytes despite costimulatory blockade (P = 0.00105 compared to Figure 2E 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]).