CD40 ligation reverses T cell tolerance in acute myeloid leukemia
Long Zhang, … , Thomas F. Gajewski, Justin Kline
Long Zhang, … , Thomas F. Gajewski, Justin Kline
Published April 24, 2013
Citation Information: J Clin Invest. 2013;123(5):1999-2010. https://doi.org/10.1172/JCI63980.
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Research Article

CD40 ligation reverses T cell tolerance in acute myeloid leukemia

Abstract

Spontaneous antigen-specific T cell responses can be generated in hosts harboring a variety of solid malignancies, but are subverted by immune evasion mechanisms active within the tumor microenvironment. In contrast to solid tumors, the mechanisms that regulate T cell activation versus tolerance to hematological malignancies have been underexplored. A murine acute myeloid leukemia (AML) model was used to investigate antigen-specific T cell responses against AML cells inoculated i.v. versus s.c. Robust antigen-specific T cell responses were generated against AML cells after s.c., but not i.v., inoculation. In fact, i.v. AML cell inoculation prevented functional T cell activation in response to subsequent s.c. AML cell challenge. T cell dysfunction was antigen specific and did not depend on Tregs or myeloid-derived suppressor cells (MDSCs). Antigen-specific TCR-Tg CD8+ T cells proliferated, but failed to accumulate, and expressed low levels of effector cytokines in hosts after i.v. AML induction, consistent with abortive T cell activation and peripheral tolerance. Administration of agonistic anti-CD40 Ab to activate host APCs enhanced accumulation of functional T cells and prolonged survival. Our results suggest that antigen-specific T cell tolerance is a potent immune evasion mechanism in hosts with AML that can be reversed in vivo after CD40 engagement.

Authors

Long Zhang, Xiufen Chen, Xiao Liu, Douglas E. Kline, Ryan M. Teague, Thomas F. Gajewski, Justin Kline

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Figure 5

Tg expression of Bcl-XL in 2C T cells rescues them from deletion in hosts with i.v. C1498.SIY cells.

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Tg expression of Bcl-XL in 2C T cells rescues them from deletion in host...
(A) CFSE-labeled 2C or 2CBCL-XL T cells were transferred into C57BL/6 mice. On day 1, mice received i.v. or s.c. C1498.SIY cells. On day 7, CFSE dilution of splenic 2C and 2CBCL-XL T cells was analyzed. Representative CFSE dilution profiles are shown. (B) Absolute numbers of 2C T cells in spleens of mice in A. *P < 0.05. (C) 2C or 2CBCL-XL T cells were transferred into mice and subsequently challenged with i.v. or s.c. C1498.SIY cells as in A. On day 7, spleen cells were restimulated with media or SIY peptide, and production of IFN-γ and TNF-α was analyzed. Numbers represent percent 2C T cells producing the indicated cytokines. (B and C) Data are representative of 2 experiments with 3 mice/group. (D) Percent 2C and 2CBCL-XL T cells in spleens and livers of mice 24 days after i.v. C1498.SIY cell challenge. Representative plots are shown. Gated areas represent percent 2C or 2CBCL-XL T cells among the entire CD8+ T cell population. Mean percent 2C and 2CBCL-XL T cells in groups of 3 mice is also shown. *P < 0.05, 2CBCL-XL versus 2C. Data are representative of 2 experiments.