Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells

Kawamura, Hiroki; Yagita, Hideo; Nisizawa, Tetsuro; Izumi, Noriaki; Miyaji, Chikako; Vance, Russell E.; Raulet, David H.; Okumura, Ko; Abo, Toru

doi:10.1002/eji.200425933

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…Administration of an agonistic mAb of NKG2A inhibited donor T cell expansion and ameliorated acute GVHD in mice (54). However, we show that T-bet −/− donor T cells express extremely low levels of CD94/NKG2A genes (Klrd1and Klrc1, respectively) ( Figure 3), and CD94 protein (Figure 4), in concert with ameliorated GVHD, suggesting that CD94/NKG2A could be biomarkers to positively predict GVHD severity.…”

Section: Discussionmentioning

confidence: 79%

T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease Through Controlling T Cell Differentiation and Function

Wang

et al. 2012

Blood

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452 Background: Allogeneic hematopoietic cell transplantation (HCT) offers great promise for the treatment of hematologic malignancies. However, HCT benefits are frequently offset by graft-versus-host disease (GVHD). Donor T cells can differentiate into Th1 or Th17 subset that contribute to GVHD. The T-box transcription factor T-bet is important for promoting the differentiation of naïve CD4+T cells into Th1 phenotype, while simultaneously inhibiting Th2 and Th17 lineage commitment. Published data indicate that donor T cells deficient for IFN-γ induce exacerbated GVHD. In contrast, our recent study showed that T cells deficient for T-bet were impaired in the induction of GVHD. Given T-bet is a master regulator for the differentiation into Th1 cells that produce IFN-γ, the underlining mechanisms accounted for the distinct outcomes caused by T-bet- versus IFN-γ-deficient donor T cells are not clear. Method: We evaluated the roles of T-bet and IFN-γ in acute GVHD induced by naïve CD4+ T cells or polarized Th17 cells using murine allogeneic bone marrow transplantation (allo-BMT) model. WT, T-bet knockout (KO) and IFN-γ KO mice on C57BL/6 (B6) background were used as donors, and lethally irradiated BALB/c mice were used as recipients. Pathologic analysis and serum cytokine detection were done 14 days after adoptive transfer of WT, T-bet–/–, and IFN-γ–/– CD4+ T cells. Using microarray technology, gene expression profile on donor T cells was analyzed 7 days after adoptive transfer by sorting donor-derived CD4+ T cells from the recipients of WT, T-bet–/– or IFN-γ–/– CD4+ T cells. Results: We compared the ability of WT, T-bet–/–, and IFN-γ–/– CD4 T cells in the induction of acute GVHD. In the comparison with WT cells, IFN-γ–/– CD4 T cells caused similar or even more severe GVHD as expected. In sharp contrast, T-bet–/– CD4 T cells induced much ameliorated GVHD, as significantly higher survival and less body weight loss were observed in the recipients of T-bet–/–T cells. Pathology study on GVHD target organs showed that recipients of T-bet–/– donor T cells had markedly reduced T cell infiltration and tissue damage in liver, gut, and skin, when compared with those of WT or IFN-γ–/– T cells. Reduced GVHD in the recipients of T-bet–/– T cells was consistent with significantly lower levels of pathogenic cytokines IFN-γ, TNF-α, and IL-2 but higher IL-10 (anti-inflammatory), IL-6 (Th17 related) and IL-4 (Th2 related) in serum as compared with those in the recipients of WT T cells. Mechanistic studies in vitro revealed that T-bet–/– CD4 T cells expressed significantly lower levels of IFN-γ, CXCR3 (Th1 specific chemokine receptor) and CD122 (T cell activation marker), but higher levels of IL-17 (Th17 cytokine) and CCR6 (Th17 specific chemokine receptor) compared with WT CD4 T cells, indicating that T-bet–/– T cells impaired in differentiating into Th1 cells and instead into Th17 cells. Given Th17 subset only is capable of causing GVHD and T-bet–/– T cells are prone to Th17-differentiation, we assessed the role of T-bet or IFN-γ in the development of GVHD by comparing the pathogenicity of in vitro polarized WT, T-bet–/– and IFN-γ–/– Th17 cells. While IFN-γ–/– Th17 cells had a comparable ability to cause GVHD compared with WT Th17 cells, T-bet–/– Th17 cells had reduced pathogenicity, and caused ameliorated GVHD. Furthermore, microarray analysis identified genes that are regulated by T-bet but independent of IFN-γ, including Cxcr3, Ccr5, Ccl3, Ccl4, Klrc1, Klrd1, Nkg7 and Pdcd1, which may explain the compromised ability of T-bet−/− not IFN-γ–/–T cells in the induction of GVHD. Conclusions: We conclude that T-bet is required for Th1 differentiation and optimal function of Th17 cells, and it can also control T cell infiltration into GVHD target organs by regulating chemokines and their receptors. Thus, failure in Th1 generation, migration and reduced activity of polarized Th17 cells are likely accounted for impaired ability of T-bet−/− CD4 T cells in the induction of acute GVHD. The current study suggests that targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD after allogeneic HCT in clinic. Disclosures: No relevant conflicts of interest to declare.

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Section: Discussionmentioning

confidence: 79%

T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease Through Controlling T Cell Differentiation and Function

Wang

et al. 2012

Blood

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“…In fact, a successful attempt to regulate inflammation via the NKG2A receptor was recently reported by Kawamura et al In their study, anti-NKG2A monoclonal antibodies were shown to restrict donor T-cell expansion and improve signs of murine acute graft-versushost disease [61]. However, it has not been shown whether these results can be extrapolated to humans and other diseases where TH1/TH2 cell and cytokine balance is important.…”

Section: Discussionmentioning

confidence: 90%

NKG2A and CD56 Are Coexpressed on Activated TH2 but Not TH1 Lymphocytes

et al. 2005

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NKG2A is commonly expressed on cytotoxic cells but has been found on activated T helper (TH) cells. In identifying novel markers differentiating between TH1 and TH2 lymphocytes, we focused on NKG2A expression. TH1 and TH2 cells were negatively isolated from healthy volunteers for microarray analysis and reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry of quiescent and activated TH1 and TH2 cells was performed. Isolates were >95% pure CD3+CD4+ cells (TH1=90.3% and TH2=84.1%). Microarrays revealed differential expression of NKG2A and NKG2C isoforms between TH1 and TH2 cells. RT-PCR indicated greater expression of NKG2A in TH2 cells (4-fold) and NKG2C in TH1 cells (3-fold). Flow studies revealed tripling of TH2 NKG2A with activation to 10.76+/-4.01% (p=0.05), a 23-fold increase in CD56 to 35+/-14.54% (p=0.03), and an increase in NKG2A+CD56+ double-positive cells to 3.04+/-1.38% (p=0.04). TH1 lymphocytes did not differ with activation. We identified co-induction of NKG2A and CD56 on activation of TH2 cells. These cells would likely bind more HLA-E and exhibit increased effector inhibition. Given that certain viruses are known to decrease MHC class I and thus HLA-E production by antigen-presenting cells, activated TH2 cells would bind less HLA-E in this scenario. This would likely result in less effector inhibition and a relatively robust TH2 response.

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“…Administration of an agonistic mAb of NKG2A inhibited donor T cell expansion and ameliorated acute GVHD in mice (54). However, we show that T-bet −/− donor T cells express extremely low levels of CD94/NKG2A genes ( Klrd1 and Klrc1 , respectively) (Figure 3), and CD94 protein (Figure 4), in concert with ameliorated GVHD, suggesting that CD94/NKG2A could be biomarkers to positively predict GVHD severity.…”

Section: Discussionmentioning

confidence: 99%

T-bet Is Critical for the Development of Acute Graft-versus-Host Disease through Controlling T Cell Differentiation and Function

Wang

et al. 2015

The Journal of Immunology

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T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ in T-cell responses in acute graft-versus-host disease (GVHD) and found that T-bet−/− T cells induced significantly less GVHD compared to WT or IFN-γ−/− counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility antigen (miHA)-mismatched models driven by CD4 T cells. T-bet−/−, but not IFN-γ−/−, CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-γ. At mRNA and protein levels, we defined several T-bet-dependent molecules that may account for the impaired ability of T-bet−/− T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-γ such as CXCR3 and PD-1, or systematic IFN-γ such as NKG2D, I-Ab, and granzyme B. Although both T-bet−/− and IFN-γ−/− CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ had a significantly reduced ability to cause GVHD. Finally, T-bet−/− T cells had compromised graft-versus-leukemia (GVL) effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in the clinic.

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Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells

Cited by 9 publications

References 40 publications

T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease Through Controlling T Cell Differentiation and Function

T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease Through Controlling T Cell Differentiation and Function

NKG2A and CD56 Are Coexpressed on Activated TH2 but Not TH1 Lymphocytes

T-bet Is Critical for the Development of Acute Graft-versus-Host Disease through Controlling T Cell Differentiation and Function

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