CXCR3 Chemokine Receptor-Ligand Interactions in the Lymph Node Optimize CD4+ T Helper 1 Cell Differentiation

Groom, Joanna R; Richmond, Julius B.; Murooka, Thomas T.; Sorensen, Elizabeth W.; Sung, Jung Hye; Bankert, Katherine; Andrian, Ulrich H. von; Moon, James; Mempel, Thorsten R.; Luster, Andrew D.

doi:10.1016/j.immuni.2012.08.016

Cited by 375 publications

(467 citation statements)

References 41 publications

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“…They postulated that sustained contact of the already primed, but uncommitted, CD4 + T cells with the CXCL10-producing DCs in the paracortex of the lymph node allowed for expansion and full Th1 polarization. Indeed, a recent study proves this point (21). CXCR3 was upregulated on CD4 + T cells in DLNs during priming, prior to clonal expansion, and contributed to migration of Ag-specific CD4 + T cells from the T cell zone to the interfollicular and medullary regions, to interaction with DCs, and to Th1 differentiation.…”

Section: Discussionmentioning

confidence: 80%

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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: Discussionmentioning

confidence: 80%

“…The resulting cluster formation between the primed CD4 + T cells and the DCs promoted Th1-type effector differentiation (20). A recent report corroborated and further clarified the mechanism by Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands which CXCL10 contributes to Th1 polarization during priming (21).…”

mentioning

confidence: 77%

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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“…The CXCR3 ligands CXCL9 and CXCL10 are often associated with Th1 responses (43) and were prominent among the cytokines detected in the dLN. The expression of both chemokines by LN stromal cells and DCs may have enhanced Th1 responses by creating a favorable environment facilitating T cell priming at the periphery of the dLN (44).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Didierlaurent

Collignon

Bourguignon

et al. 2014

The Journal of Immunology

219

198

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Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCIIhigh dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCIIhigh dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.

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“…The additional release of CXCL10 would further increase recruitment of T cells to the local area. A recently published study demonstrated that CXCL10 production by DC is important in DC–T cell interactions during priming of T cells in the lymph node 24. It is possible that CXCL10 production by APCs is similarly important for reactivation and further recruitment of memory T cells in the brain in PND, and that CXCL10 production by responding T cells augments the response.…”

Section: Discussionmentioning

confidence: 99%

“…CXCL10 and the CXCR3 receptor have been proposed to work in an inflammation‐promoting loop in allergy27 and to modulate IFNγ production in EAE 28. CXCR3 has been suggested not only to play a role in T cell priming in the lymph node24 but also in the recruitment of T cells into peripheral target tissues 29. Taken together, these data suggest that the high concentration of CXCL10 present in PND patient CSF may be due to production of this chemokine by infiltrating autoimmune T cells interacting with APCs in the CNS 30.…”

Section: Discussionmentioning

confidence: 99%

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Roberts

Blachère

Frank

et al. 2015

Annals of Neurology

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ObjectiveParaneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high‐titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients.MethodsCSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow‐up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen.ResultsHere we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3+ cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen‐specific cognate interactions between T cells and antigen‐presenting cells (APCs) when interferon‐γ (IFNγ) receptors were present on the T cell.InterpretationThese results support a model in which antigen‐specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation. Ann Neurol 2015;78:619–629

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CXCR3 Chemokine Receptor-Ligand Interactions in the Lymph Node Optimize CD4+ T Helper 1 Cell Differentiation

Cited by 375 publications

References 41 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

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

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