Chemokine Receptor CCR7 Contributes to a Rapid and Efficient Clearance of Lytic Murine γ-Herpes Virus 68 from the Lung, Whereas Bronchus-Associated Lymphoid Tissue Harbors Virus during Latency

Kocks, Jessica R.; Adler, Heiko; Danzer, Heike; Hoffmann, Katharina; Jonigk, Danny; Lehmann, Ulrich; Förster, Reinhold

doi:10.4049/jimmunol.0801826

Cited by 30 publications

(30 citation statements)

References 36 publications

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“…Our findings are similar to those of a study in a murine Listeria monocytogenes infection model, where efficient priming of CD8 ϩ T cells was found to be Ccr7 independent (36). In contrast in gamma herpesvirus 68 -infected mice, a temporally efficient activation of T cells and viral clearance were Ccr7 dependent (37). Thus, the role of Ccr7 in T cell activation appears to be context and model dependent.…”

Section: Discussionsupporting

confidence: 80%

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Bardina

Brown

Michlmayr

et al. 2017

J Virol

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West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. IMPORTANCEIn this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.KEYWORDS arbovirus, cell trafficking, chemokine receptors, chemokines, hostpathogen interactions, leukocytes, neuroimmunology, viral pathogenesis W est Nile virus (WNV) is a mosquito-transmitted flavivirus that was introduced into the United States in 1999 (1). Since then, the virus has spread rapidly across the continent and has become the leading cause of arthropod-borne virus-induced encephalitis in the United States. WNV is a significant public health concern due to the unpredictable nature of annual disease outbreaks and the lack of specific therapeutics and vaccines for human use (2). In humans, WNV is transmitted through the bite of an infected mosquito. The outcome of infection ranges from asymptomatic to severe neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis (3)(4)(5)

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Section: Discussionsupporting

confidence: 80%

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Bardina

Brown

Michlmayr

et al. 2017

J Virol

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“…CCL19 and CCL21 expression has been identified in peripheral organs, such as the lung (27,43), but their role in host defense is not fully understood. Previous studies employing models of pulmonary infection have shown that CCR7 deficiency leads to impaired host defense (1,6,15,18,19,22,31). However, we demonstrated that CCR7 deficiency FIG.…”

Section: Discussioncontrasting

confidence: 52%

“…CCL19 and CCL21 are expressed primarily in secondary lymphoid organs, but they are also expressed in other tissues, such as the gastrointestinal tract, kidney, and lung (27,43). Previous studies demonstrated that disruption of cellular interactions coordinated through CCR7 impaired T cell function and increased susceptibility to viral infections (10,12,19,29). These results were attributed to disruption of lymph node architecture and impaired T cell and DC migration to the lymph node, which prevented efficient antigen presentation to naïve T cells.…”

mentioning

confidence: 88%

“…Many studies employed viral pathogens (6,15,18,19,31), while other studies investigated infections by Listeria monocytogenes (22) or Leishmania donovani (1). Each of these studies indicated that clearance of infection is delayed or impaired in plt or Ccr7 Ϫ/Ϫ mice.…”

Section: Fig 5 Neutrophils Recovered After P Aeruginosa Infection mentioning

confidence: 99%

“…Previous studies have examined the role of CCR7 or its ligands in pulmonary infections (15,17,19), but how CCR7 shapes the immune response to pathogen exposures in the lung remains unclear. In this study, we investigated whether cellular migration and activation due to CCR7 signaling were required for the host defense against acute pulmonary P. aeruginosa infection.…”

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confidence: 99%

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CCR7 Deficiency Leads to Leukocyte Activation and Increased Clearance in Response to Pulmonary Pseudomonas aeruginosa Infection

Eppert¹,

Motz²,

Wortham³

et al. 2010

Infect Immun

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CCR7 is a chemokine receptor expressed on the surfaces of T cells, B cells, and mature dendritic cells that controls cell migration in response to the cognate ligands CCL19 and CCL21. CCR7 is critical for the generation of an adaptive T cell response. However, the roles of CCR7 in the host defense against pulmonary infection and innate immunity are not well understood. We investigated the role of CCR7 in the host defense against acute pulmonary infection with Pseudomonas aeruginosa. We intranasally infected C57BL/6 mice with P. aeruginosa and characterized the expression of CCR7 ligands and the surface expression of CCR7 on pulmonary leukocytes. In response to infection, expression of CCL19 and expression of CCL21 were oppositely regulated, and myeloid dendritic cells upregulated CCR7 expression. We further examined the effects of CCR7 deficiency on the inflammatory response to P. aeruginosa infection. We infected Ccr7 ؊/؊ and wild-type mice with P. aeruginosa and characterized the accumulation of pulmonary leukocytes, production of proinflammatory mediators, neutrophil activation, and bacterial clearance. CCR7 deficiency led to an accumulation of myeloid dendritic cells and T cells in the lung in response to infection. CCR7 deficiency resulted in higher expression of CD80 and CD86 on dendritic cells; increased production of interleukin-12/23p40 (IL-12/23p40), gamma interferon (IFN-␥), and IL-1␣; increased neutrophil respiratory burst; and, ultimately, increased clearance of acute P. aeruginosa infection. In conclusion, our results suggest that CCR7 deficiency results in a heightened proinflammatory environment in response to acute pulmonary P. aeruginosa infection and contributes to more efficient clearance.

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Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

Wang,

et al. 2024

MedComm

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Cancer is a major cause of death globally, and traditional treatments often have limited efficacy and adverse effects. Immunotherapy has shown promise in various malignancies but is less effective in tumors with low immunogenicity or immunosuppressive microenvironment, especially sarcomas. Tertiary lymphoid structures (TLSs) have been associated with a favorable response to immunotherapy and improved survival in cancer patients. However, the immunological mechanisms and clinical significance of TLS in malignant tumors are not fully understood. In this review, we elucidate the composition, neogenesis, and immune characteristics of TLS in tumors, as well as the inflammatory response in cancer development. An in‐depth discussion of the unique immune characteristics of TLSs in lung cancer, breast cancer, melanoma, and soft tissue sarcomas will be presented. Additionally, the therapeutic implications of TLS, including its role as a marker of therapeutic response and prognosis, and strategies to promote TLS formation and maturation will be explored. Overall, we aim to provide a comprehensive understanding of the role of TLS in the tumor immune microenvironment and suggest potential interventions for cancer treatment.

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Chemokine Receptor CCR7 Contributes to a Rapid and Efficient Clearance of Lytic Murine γ-Herpes Virus 68 from the Lung, Whereas Bronchus-Associated Lymphoid Tissue Harbors Virus during Latency

Cited by 30 publications

References 36 publications

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

CCR7 Deficiency Leads to Leukocyte Activation and Increased Clearance in Response to Pulmonary Pseudomonas aeruginosa Infection

Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

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