Chemokine receptor CXCR3 facilitates CD8+ T cell differentiation into short-lived effector cells leading to memory degeneration

Kurachi, Makoto; Kurachi, Junko; Suenaga, Fumiko; Tsukui, Tohru; Abe, Jun; Ueha, Satoshi; Tomura, Michio; Sugihara, Kei; Takamura, Shiki; Kakimi, Kazuhiro; Matsushima, Kouji

doi:10.1084/jem.20102101

Cited by 175 publications

(198 citation statements)

References 80 publications

(138 reference statements)

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“…We now add that CXCL10 performs such a function for CD8 + T cells, in accordance with a recent finding that CXCL10 produced by DCs can support the generation of a CD8 + T cell response (50). Interestingly, recent findings on the role of CXCR3 in fate determination of primed CD8 + T cells further support this notion (51,52). CXCR3 binds CXCL9, CXCL10, and CXCL11, but C57BL/6 mice only express CXCL9 and CXCL10 (52).…”

Section: Discussionsupporting

confidence: 90%

“…This redistribution was impaired when the CD8 + T cells lacked expression of CXCR3. It was suggested that this redistribution within the priming organ and the consequent longer or shorter contact with Ag-presenting DCs determined the long-term fate of the CD8 + T cells (51,52). Our data are in full agreement with the concept that CXCR3 and CXCL10 play a role in the localization of primed CD8 + T cells at the site of priming and, thereby, affect the CD8 + T cell response.…”

Section: Discussionsupporting

confidence: 89%

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CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

Peperzak

Veraar

Xiao

et al. 2013

The Journal of Immunology

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Various cell types can produce the chemokine CXCL10 in response to IFN-γ stimulation. CXCL10 is generally viewed as a proinflammatory chemokine that promotes recruitment of CD8+ and Th1-type CD4+ effector T cells to infected or inflamed nonlymphoid tissues. We show that CXCL10 plays a role during CD8+ T cell priming in the mouse. Genome-wide expression profiling revealed the Cxcl10 gene as a target of CD27/CD70 costimulation in newly activated CD8+ T cells. CD27/CD70 costimulation is known to promote activated T cell survival, but CXCL10 did not affect survival or proliferation of primed CD8+ T cells in vitro. Accordingly, CXCL10 could not fully rescue CD27 deficiency in mice infected with influenza virus. Rather, CXCL10 acted as chemoattractant for other activated CD8+ T cells. It signaled downstream of CD27 in a paracrine fashion to promote generation of the CD8+ effector T cell pool in the Ag-draining lymph nodes. Consistently, CD8+ T cells required expression of the CXCL10 receptor CXCR3 for their clonal expansion in a CD27/CD70-dependent peptide-immunization model. Our findings indicate that CXCL10, produced by primed CD8+ T cells in response to CD27/CD70 costimulation, signals to other primed CD8+ T cells in the lymph node microenvironment to facilitate their participation in the CD8+ effector T cell pool.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

Peperzak

Veraar

Xiao

et al. 2013

The Journal of Immunology

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“…(9,10) In particular, recent studies have shown that CXCR3 chemokine receptors are involved in promoting CD8 + T cell commitment to an effector fate rather than a memory fate. (11,12) The reaction was then developed with 100 μL of TMB liquid substrate solution (T4444, Sigma) at room temperature for 30 min in the dark and stopped by the addition of 1 M sulfuric acid. The absorbance at 450 nm was measured by an ELISA plate reader (Tecan Sunrise).…”

Section: Construction Of Np Expression Vector and Expression And Purimentioning

confidence: 99%

Temporary CXCR3 and CCR5 Antagonism Following Vaccination Enhances Memory CD8 T Cell Immune Responses

Zhang

Tian

et al. 2016

Mol Med

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Although current vaccination strategies have been successful at preventing a variety of human diseases, attempts at vaccinating against some pathogens such as AIDS and tuberculosis (TB) have been more problematic, largely because abnormally high numbers of antigen-specific CD8 + T cells are required for protection. This study assessed the effect on host immune response of temporarily dampening the chemokine receptors CXCR3 and CCR5 after vaccination by administration of TAK-779, a small-molecule CXCR3 and CCR5 antagonist commonly used to inhibit HIV infection. Our results showed that use of TAK-779 enhanced memory CD8 + T cell immune responses both qualitatively and quantitatively. Treatment with TAK-779 following vaccination of an influenza virus antigen resulted in enhanced memory generation, with more CD8 + CD127 + memory precursors and fewer terminally differentiated effector CD8 + CD69 + T cells. These memory T cells were able to become IFN-γ-secreting effector cells when re-encountering the same antigen, which can further enhance the efficacy of vaccination. The mice vaccinated in the presence of TAK-779 were better protected upon influenza virus challenge than the controls. These results show that vaccination, while temporarily inhibiting chemokine receptors CXCR3 and CCR5 by TAK-779, could be a promising strategy to generate large numbers of protective memory CD8 + T cells.

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“…For in vivo memory generation, B6 mice were adoptively transferred with CD8 + T cells (1 3 10 4 ) from CD45.1 Rag2 KO OT-I mice and infected with PbA-OVA or LM-OVA (18). Postinfection with PbA-OVA, mice were treated with chloroquine and sulfadiadne (Sigma-Aldrich) for 2 wk between days 6 (parasitemia 2.1-12.1%) and 20 as described previously with slight modification (19).…”

Section: Generation Of Memory Cellsmentioning

confidence: 99%

Development of Memory CD8+ T Cells and Their Recall Responses during Blood-Stage Infection with Plasmodium berghei ANKA

Miyakoda

Kimura

Honma

et al. 2012

The Journal of Immunology

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Conditions required for establishing protective immune memory vary depending on the infecting microbe. Although the memory immune response against malaria infection is generally thought to be relatively slow to develop and can be lost rapidly, experimental evidence is insufficient. In this report, we investigated the generation, maintenance, and recall responses of Ag-specific memory CD8+ T cells using Plasmodium berghei ANKA expressing OVA (PbA-OVA) as a model system. Mice were transferred with OVA-specific CD8+ T (OT-I) cells and infected with PbA-OVA or control Listeria monocytogenes expressing OVA (LM-OVA). Central memory type OT-I cells were maintained for >2 mo postinfection and recovery from PbA-OVA. Memory OT-I cells produced IFN-γ as well as TNF-α upon activation and were protective against challenge with a tumor expressing OVA, indicating that functional memory CD8+ T cells can be generated and maintained postinfection with P. berghei ANKA. Cotransfer of memory OT-I cells with naive OT-I cells to mice followed by infection with PbA-OVA or LM-OVA revealed that clonal expansion of memory OT-I cells was limited during PbA-OVA infection compared with expansion of naive OT-I cells, whereas it was more rapid during LM-OVA infection. The expression of inhibitory receptors programmed cell death-1 and LAG-3 was higher in memory-derived OT-I cells than naive-derived OT-I cells during infection with PbA-OVA. These results suggest that memory CD8+ T cells can be established postinfection with P. berghei ANKA, but their recall responses during reinfection are more profoundly inhibited than responses of naive CD8+ T cells.

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Chemokine receptor CXCR3 facilitates CD8+ T cell differentiation into short-lived effector cells leading to memory degeneration

Abstract: CXCR3 regulates CD8+ T cell recruitment to sites of inflammation, thus dictating CD8+ T cell contraction and subsequent effector/memory cell fate.

Cited by 175 publications

References 80 publications

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

Temporary CXCR3 and CCR5 Antagonism Following Vaccination Enhances Memory CD8 T Cell Immune Responses

Development of Memory CD8+ T Cells and Their Recall Responses during Blood-Stage Infection with Plasmodium berghei ANKA

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