CD40 ligation reverses T cell tolerance in acute myeloid leukemia
Long Zhang, Xiufen Chen, Xiao Liu, Douglas E. Kline, Ryan M. Teague, Thomas F. Gajewski, Justin Kline
Long Zhang, Xiufen Chen, Xiao Liu, Douglas E. Kline, Ryan M. Teague, Thomas F. Gajewski, Justin Kline
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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 4

SIY-specific 2C T cells undergo abortive peripheral tolerance in mice with i.v. C1498.SIY.

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SIY-specific 2C T cells undergo abortive peripheral tolerance in mice wi...
CFSE-labeled 2C T cells (4 × 106) were adoptively transferred into C57BL/6 mice, followed 1 day later by inoculation with i.v. or s.c. C1498.SIY cells. (A) On day 7, 2C T cells were enumerated. *P < 0.05, i.v. versus s.c. Data are representative of 4 experiments with 3–5 mice/group. (B) Representative FACS plots from mice in A. Gated areas represent percent 2C T cells among the entire CD8+ T cell population. (C) Mean percent 2C T cells from mice in A. *P < 0.05, i.v. versus s.c. (D) CFSE dilution of 2C T cells from mice in A. (E) Mice received 2C T cells and C1498.SIY challenge as in A. On day 7, spleen and LN cells were restimulated with media or SIY peptide. Production of IFN-γ by 2C T cells was analyzed. Numbers represent percent IFN-γ+ 2C T cells. (F) Numbers of IFN-γ–producing 2C T cells after i.v. or s.c. C1498.SIY cell challenge. #P = 0.10, *P < 0.05, i.v. versus s.c. (E and F) Data are representative of 3 experiments with 3 mice/group.