IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma
Zhi-Zhang Yang, … , Thomas E. Witzig, Stephen M. Ansell
Zhi-Zhang Yang, … , Thomas E. Witzig, Stephen M. Ansell
Published March 19, 2012
Citation Information: J Clin Invest. 2012;122(4):1271-1282. https://doi.org/10.1172/JCI59806.
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Research Article Oncology

IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma

Abstract

The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ–independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12– and TIM-3–mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients.

Authors

Zhi-Zhang Yang, Deanna M. Grote, Steven C. Ziesmer, Toshiro Niki, Mitsuomi Hirashima, Anne J. Novak, Thomas E. Witzig, Stephen M. Ansell

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Figure 6

Effect of blockade of TIM-3 signaling on restoration of IL-12–mediated T cell dysfunction.

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Effect of blockade of TIM-3 signaling on restoration of IL-12–mediated T...
(A) Representative dot plots showing IL-2 and IFN-γ production in CD4+ T cells treated with either anti–TIM-3 Ab or isotype IgG in the presence of IL-12 at different time points (n = 5). IL-2 and IFN-γ production were detected by intracellular staining. (B) Representative histograms showing proliferation of CD4+ T cells treated with or without anti–TIM-3 Abs or isotype IgG control. Proliferation was measured by CFSE staining and expressed as the number of CFSEdim cells. (C) Representative dot plots showing IL-2 (upper panels) and IFN-γ (lower panels) production in TIM-3– or TIM-3+ CD4+ T cells treated with either anti–TIM-3 Abs or isotype IgG in the presence of IL-12 at different time points (n = 5). IL-2 and IFN-γ production were detected by intracellular staining. Percentage of total cell numbers are indicated (A and C). (D) A summary of frequency of IL-2– or IFN-γ–producing cells in TIM-3– or TIM-3+ CD4+ T cells treated with either anti–TIM-3 Ab (+) or isotype IgG (–) in the presence of IL-12 for 10 days (n = 5). IL-2 or IFN-γ production in TIM-3– or TIM-3+ CD4+ T cells was measured by intracellular staining and calculated as percentage of total CD4+ cells. Data are shown as mean ± SD. *P < 0.05.