Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection
Joel Trambley, … , Thomas C. Pearson, Christian P. Larsen
Joel Trambley, … , Thomas C. Pearson, Christian P. Larsen
Published December 15, 1999
Citation Information: J Clin Invest. 1999;104(12):1715-1722. https://doi.org/10.1172/JCI8082.
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Article

Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Abstract

Simultaneous blockade of the CD40 and CD28 costimulatory pathways is an effective treatment strategy to promote allograft acceptance but does not lead to indefinite allograft survival. The immune mechanisms responsible for costimulation-independent rejection are not defined. Here we have studied the rejection responses of murine C57BL/6 recipients, which we show to be relatively resistant to inhibition by combined CD40/CD28 blockade. We demonstrate that asialo GM1+ CD8+ cells play a critical role in this costimulation blockade–resistant rejection. These results provide new insights into the costimulatory requirements for T-cell subsets and demonstrate for the first time that combined blockade of the CD40 and CD28 pathways does not adequately inhibit CD8-mediated skin allograft rejection. Furthermore, we provide evidence that asialo GM1 is a potentially important therapeutic target for CD8-dependent immune responses.

Authors

Joel Trambley, Adam W. Bingaman, Angello Lin, Eric T. Elwood, Seung-Yeun Waitze, Jongwon Ha, Megan M. Durham, Matthias Corbascio, Shannon R. Cowan, Thomas C. Pearson, Christian P. Larsen

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CD8+ T cells mediate costimulation blockade–resistant rejection. B6 reci...
CD8+ T cells mediate costimulation blockade–resistant rejection. B6 recipients were depleted of CD4 or CD8 cells with GK1.5 or TIB105, respectively (100 μg on days –3, –2, and –1 and weekly until rejection) or left undepleted. Recipient mice were transplanted with Balb/c skin allografts on day 0 and treated with costimulation blockade alone (CTLA4-Ig, anti-CD40L, 500 μg on days 0, 2, 4, and 6) or left untreated. (a) Costimulation blockade has no effect on CD8-mediated rejection. Untreated recipients depleted of CD4 cells (MST 16 days; n = 7) had minimally prolonged allograft survival compared with undepleted mice without treatment (MST 9 days; n = 6). Treatment with costimulation blockade did not prolong allograft survival in recipients depleted of CD4 cells (MST 18 days; n = 7) compared with costimulation blockade treatment of undepleted mice (MST 20.5 days; n = 6). (b) Costimulation blockade significantly inhibits CD4-mediated allograft rejection. In the same experiment as a, depicted on a separate graph for clarity, treatment of CD8-depleted recipients with costimulation blockade (MST 67 days; n = 5) significantly prolonged allograft survival compared with undepleted recipients treated with costimulation blockade (MST 20.5 days; n = 6; P < 0.01) or recipients treated with anti-CD8 alone (MST 11 days; n = 7).