CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

Hickman, Heather D.; Reynoso, Glennys V.; Ngudiankama, Barbara F.; Cush, Stephanie S.; Gibbs, James S.; Bennink, Jack R.; Yewdell, Jonathan W.

doi:10.1016/j.immuni.2015.02.009

Cited by 190 publications

(191 citation statements)

References 42 publications

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“…Importantly though, quantitative analysis of the data and subsequent computer simulations based on these experimental data demonstrate that there is a small preference to migrate toward sites of infection. As expected, and on the basis of the recent findings by Hickman et al (7), this preference depends on CXCR3 expression on T cells and can be influenced by disturbance of CXCR3 ligands. Furthermore, this preference translates to a marked increase in the efficiency with which effector T cells accumulate at the sites of infection.…”

supporting

confidence: 84%

“…Several studies have examined the interaction between CTLs and target cells at sites of infection (4)(5)(6). In another recent study by Hickman et al (7), it was shown that expression of the chemokine receptor CXCR3 on T cells assists in the localization, killing, and control of vaccinia virus (VV) infection. However, the exact search strategy by which CXCR3 expression helps T cells to detect virus-infected targets has not yet been elucidated.…”

mentioning

confidence: 99%

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Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Ariotti

Beltman

Borsje

et al. 2015

The Journal of Immunology

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It is well established how effector T cells exit the vasculature to enter the peripheral tissues in which an infection is ongoing. However, less is known regarding how CTLs migrate toward infected cells after entry into peripheral organs. Recently, it was shown that the chemokine receptor CXCR3 on T cells has an important role in their ability to localize infected cells and to control vaccinia virus infection. However, the search strategy of T cells for virus-infected targets has not been investigated in detail and could involve chemotaxis toward infected cells, chemokinesis (i.e., increased motility) combined with CTL arrest when targets are detected, or both. In this study, we describe and analyze the migration of CTLs within HSV-1–infected epidermis in vivo. We demonstrate that activated T cells display a subtle distance-dependent chemotaxis toward clusters of infected cells and confirm that this is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, computer simulations based on short-term experimental data, combined with subsequent long-term imaging indicate that this behavior is crucial for efficient target localization and T cell accumulation at effector sites. Thus, chemotactic migration of effector T cells within peripheral tissue forms an important factor in the speed with which T cells are able to arrive at sites of infection.

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supporting

confidence: 84%

mentioning

confidence: 99%

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Ariotti

Beltman

Borsje

et al. 2015

The Journal of Immunology

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“…6E), we observed an average of a 22-fold increase in bacterial burden. A similar phenomenon was recently reported where CXCR3 expression on effector CD8 αβ T cells was critical for their ability to migrate locally in the skin to eliminate virus-infected cells (32).…”

Section: Discussionsupporting

confidence: 78%

IL-17A–producing resident memory γδ T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection

Romagnoli

Sheridan

Pham

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Memory γδ T cells are important for the clearance of Listeria monocytogenes infection in the intestinal mucosa. However, the mechanisms by which memory γδ T cells provide protection against secondary oral infection are poorly understood. Here we used a recombinant strain of L. monocytogenes that efficiently invades the intestinal epithelium to show that Vγ4 + memory γδ T cells represent a resident memory (Trm) population in the mesenteric lymph nodes (MLNs). The γδ Trm exhibited a remarkably static pattern of migration that radically changed following secondary oral L. monocytogenes infection. The γδ Trms produced IL-17A early after rechallenge and formed organized clusters with myeloid cells surrounding L. monocytogenes replication foci only after a secondary oral infection. Antibody blocking studies showed that in addition to IL-17A, the chemokine receptor C-X-C chemokine receptor 3 (CXCR3) is also important to enable the local redistribution of γδ Trm cells and myeloid cells specifically near the sites of L. monocytogenes replication within the MLN to restrict bacterial growth and spread. Our findings support a role for γδ Trms in orchestrating protective immune responses against intestinal pathogens.

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“…We next determined whether the CXCR3 signaling pathway might also be crucial in the effector function of HSV-specific CD8 ϩ T cells in the cornea and TG. Since HLA Tg mice deficient for CXCR3 (i.e., CXCR3 Ϫ/Ϫ ) are not available, we turned to the CXCR3-deficient mice that are available on the B6 genetic background and their wild-type (WT) B6 control littermates (33,34). Both WT and CXCR3 Ϫ/Ϫ deficient mice develop H2 b -restricted CD8 ϩ T cells specific to the immunodominant HSV-1 gB epitope (gB [498][499][500][501][502][503][504][505] ) following ocular infection with HSV-1.…”

Section: Resultsmentioning

confidence: 99%

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8 ϩ T cells play a critical role in preventing HSV-1 reactivation from TG and subsequent virus shedding in tears that trigger recurrent corneal herpetic disease. The CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) chemokine pathway promotes T cell immunity to many viral pathogens, but its importance in CD8 ϩ T cell immunity to recurrent herpes has been poorly elucidated. In this study, we determined how the CXCL10/CXCR3 pathway affects TG-and cornea-resident CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease using a well-established murine model in which HSV-1 reactivation was induced from latently infected TG by UV-B light. Following UV-B-induced HSV-1 reactivation, a significant increase in both the number and function of HSV-specific CXCR3 ϩ CD8 ϩ T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10 Ϫ/Ϫ or CXCR3 Ϫ/Ϫ deficient mice. This increase was associated with a significant reduction in both virus shedding and recurrent corneal herpetic disease. Furthermore, delivery of exogenous CXCL10 chemokine in TG of CXCL10 Ϫ/Ϫ mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8 ϩ T cells (T EM ) and tissue-resident memory CD8 ϩ T cells (T RM ), but not of central memory CD8 ϩ T cells (T CM ), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10 Ϫ/Ϫ deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8 ϩ T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCE We determined how the CXCL10/CXCR3 pathway affects CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease. Using a wellestablished murine model, in which HSV-1 reactivation in latently infected trigeminal ganglia was induced by UV-B light, we demonstrated that lack of either CXCL10 chemokine or its CXCR3 receptor compromised the mobilization of functional CD8 ϩ T EM and CD8 ϩ T RM cells within latently infected trigeminal ganglia following virus reactivation. This lack of T cell mobilization was associated with an increase in recurrent ocular herpesvirus infection and disease. Inversely, augmenting the amount of

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CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

Cited by 190 publications

References 42 publications

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

IL-17A–producing resident memory γδ T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

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CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells

Cited by 190 publications

References 42 publications

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

IL-17A–producing resident memory γδ T cells orchestrate the innate immune response to secondary oral Listeria monocytogenes infection

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

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CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease