CCR7 Plays No Appreciable Role in Trafficking of Central Memory CD4 T Cells to Lymph Nodes

Lugt, Bryan Vander; Tubo, Noah J.; Nizza, Suzanne; Boes, Marianne; Malissen, Bernard; Fuhlbrigge, Robert C.; Kupper, Thomas S.; Campbell, James J.

doi:10.4049/jimmunol.1200938

Cited by 32 publications

(28 citation statements)

References 50 publications

(93 reference statements)

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“…Therefore, Langerhans cells would also be nearly absent from the draining lymph node during infection as well. Indeed, Langerhans cells require Ccr7 to migrate into lymph nodes (39), and during homeostasis and inflammatory conditions, Langerhans cells are absent in the draining lymph node in Ccr7-deficient mice (17,(40)(41)(42). Therefore, the current evidence indicates that Langerhans cells would be an unlikely source of viral trafficking to the draining lymph nodes in our study.…”

Section: Discussionmentioning

confidence: 65%

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: Discussionmentioning

confidence: 65%

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Bardina

Brown

Michlmayr

et al. 2017

J Virol

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“…TEM represented a significant fraction (>20–50%) of T cells in lymphoid tissues, while TEMRA cells (exclusively CD8 + ) were found only in blood, spleen and lung, suggesting a distinct circulatory niche for this subset. Recent studies in mice showing that memory T cell migration is not driven by CCR7 expression (Vander Lugt et al, 2013), and that tissue-homing of CD8 + T cells during allograft rejection occurs independent of chemokine receptor signaling (Walch et al, 2013), further suggest that memory T cell localization is not driven by CCR7 expression. In addition, few CCR7 + TCM cells were found among CD8 + T populations in multiple lymph nodes from over 50 individuals studied, indicating that lymphoid CD8 + T cell memory does not persist as canonical TCM cells.…”

Section: Discussionmentioning

confidence: 99%

Spatial Map of Human T Cell Compartmentalization and Maintenance over Decades of Life

Thome

Yudanin

Ohmura

et al. 2014

Cell

486

568

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SUMMARY Mechanisms for human memory T cell differentiation and maintenance have largely been inferred from studies of peripheral blood, though the majority of T cells are found in lymphoid and mucosal sites. We present here a multidimensional, quantitative analysis of human T cell compartmentalization and maintenance over six decades of life in blood, lymphoid and mucosal tissues obtained from 56 individual organ donors. Our results reveal that the distribution and tissue residence of naïve, central and effector memory, and terminal effector subsets is contingent on both their differentiation state and tissue localization. Moreover, T cell homeostasis driven by cytokine or TCR-mediated signals is different in CD4+ or CD8+ T cell lineages, varies with their differentiation stage and tissue localization, and cannot be inferred from blood. Our data provide an unprecedented spatial and temporal map of human T cell compartmentalization and maintenance, supporting distinct pathways for human T cell fate determination and homeostasis.

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“…The recent identification and characterization of the T RM subset of memory CD8 + T cells has generated considerable interest in the field and suggests there are probably additional, specialized memory CD8 + T cells beyond the broadly defined T CM and T EM subsets. In fact, recent evidence suggests that memory CD4 + T cells do not use CCR7 for homing to lymph nodes and CCR7-deficiency only has minimal effect on memory CD8 + T cell lymph node homing [117]. Therefore, even the most fundamental principles of memory CD8 + T cell trafficking are still being disputed in the literature.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of CD8+ T cell trafficking and localization

Nolz

2015

Cell. Mol. Life Sci.

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Cytotoxic CD8+ T cells are potent mediators of host protection against disease due to their ability to directly kill cells infected with intracellular pathogens and produce inflammatory cytokines at the site of infection. To fully achieve this objective, naïve CD8+ T cells must be able to survey the entire body for the presence of foreign or “non-self” antigen that is delivered to draining lymph nodes following infection or tissue injury. Once activated, CD8+ T cells undergo many rounds of cell division, acquire effector functions, and are no longer restricted to the circulation and lymphoid compartments like their naïve counterparts, but rather are drawn to inflamed tissues in order to combat infection. As CD8+ T cells transition from naïve to effector to memory populations, this is accompanied by dynamic changes in the expression of adhesion molecules and chemokine receptors that ultimately dictate their localization in vivo. Thus, an understanding of the molecular mechanisms regulating CD8+ T cell trafficking and localization are critical for vaccine design, control of infectious diseases, treatment of autoimmune disorders, and cancer immunotherapy.

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CCR7 Plays No Appreciable Role in Trafficking of Central Memory CD4 T Cells to Lymph Nodes

Cited by 32 publications

References 50 publications

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Spatial Map of Human T Cell Compartmentalization and Maintenance over Decades of Life

Molecular mechanisms of CD8+ T cell trafficking and localization

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