CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism

Protul Shrikant, Alexander Khoruts, Matthew F Mescher

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264 Scopus citations


A tumor-specific CD8+ T cell response was studied using adoptive transfer of OT-I TCR transgenic cells. Upon i.p. challenge with E.G7 tumor, OT-I cells undergo CD4+ T cell-independent expansion at the tumor site and develop lytic function. Before tumor elimination, however, they leave the peritoneal cavity (PC) and appear in the LN and spleen where they exhibit 'split anergy' and cannot further proliferate to antigen. Administering anti- CTLA-4 mAb early caused sustained OT-1 expansion in the PC, and late administration caused the OT-I cells to return to the PC and further expand; in both cases, tumor was controlled. These effects required CD4+ T cells and IL-2 and appear to result from reversal of the nonresponsive state of the CD8+ T cells.

Original languageEnglish (US)
Pages (from-to)483-493
Number of pages11
Issue number4
StatePublished - Oct 1999

Bibliographical note

Funding Information:
We thank Marc Jenkins for helpful advice and discussion and Dan Mueller for critical reading of the manuscript. We also thank Debra Lins for expert technical assistance. P. S. was supported by a National Multiple Sclerosis Society fellowship (FG 1218-A-1), and A. K. is a Howard Hughes Medical Institute Postdoctoral Physician Fellow. This work was supported by National Institute of Health Grants AI34824 and AI35296.


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