Regulation of Antigen-Experienced T Cells: Lessons from the Quintessential Memory Marker CD44

Despite the widespread use of the cell-surface receptor CD44 as a marker for antigen (Ag)-experienced, effector and memory T cells, surprisingly little is known regarding its function on these cells. The best-established function of CD44 is the regulation of cell adhesion and migration. As such, the interactions of CD44, primarily with its major ligand, the extracellular matrix (ECM) component hyaluronic acid (HA), can be crucial for the recruitment and function of effector and memory T cells into/within inflamed tissues. However, little is known about the signaling events following engagement of CD44 on T cells and how cooperative interactions of CD44 with other surface receptors affect T cell responses. Recent evidence suggests that the CD44 signaling pathway(s) may be shared with those of other adhesion receptors, and that these provide contextual signals at different anatomical sites to ensure the correct T cell effector responses. Furthermore, CD44 ligation may augment T cell activation after Ag encounter and promote T cell survival, as well as contribute to regulation of the contraction phase of an immune response and the maintenance of tolerance. Once the memory phase is established, CD44 may have a role in ensuring the functional fitness of memory T cells. Thus, the summation of potential signals after CD44 ligation on T cells highlights that migration and adhesion to the ECM can critically impact the development and homeostasis of memory T cells, and may differentially affect subsets of T cells. These aspects of CD44 biology on T cells and how they might be modulated for translational purposes are discussed

Matrix Metalloprotease 9 Mediates Neutrophil Migration into the Airways in Response to Influenza Virus-Induced Toll-Like Receptor Signaling

The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP) 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9-deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR) signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFα were reduced in the Myd88−/− airways. Furthermore, TNFα induced MMP9 secretion by neutrophils and blocking TNFα in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes

The role of the host genotype in the early pathogenesis of Marek's Disease after natural infection

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Location, location, location: the impact of migratory heterogeneity on T cell function

T cell migration is crucial for an effective adaptive immune response to invading pathogens. Naive and memory T cells encounter pathogen antigens, become activated and differentiate into effector cells in secondary lymphoid tissues, and then migrate to the site(s) of infection where they exert effector activities that control and eliminate pathogens. To achieve activation, efficient effector function, and good memory formation, T cells must traffic between lymphoid and non-lymphoid tissues within the body. This complex process is facilitated by chemokine receptors, selectins, CD44, and integrins that mediate the interactions of T cells with the environment. The expression patterns of these migration receptors (MR) dictate the tissues into which the effector T cells migrate and enable them to occupy specific niches within the tissue. While MR have been considered primarily to facilitate cell movement, we highlight how the heterogeneity of signaling through these receptors influences the function and fate of T cells in situ. We explore what drives MR expression heterogeneity, how this affects migration, and how this impacts T cell effector function and memory formation

Route of challenge is critical in determining the clinical outcome of infection with a very virulent oncogenic herpesvirus, Marek's disease virus

The majority of experimental studies examining Marek's disease virus infection have used parenteral injection of cell-associated virus. The aim of this study was to examine whether the route of entry of virus was critical in determining the outcome of infection. Susceptible (L7) and resistant (L6) White Leghorn chickens were infected with a very virulent Marek's disease virus, RB1B, by either the intra-abdominal or intra-tracheal route. Birds infected by the intra-tracheal route had earlier, higher or more sustained blood, spleen and lung viral concentrations than those infected by the intra-abdominal route. L7 birds had higher viral loads than L6 birds infected by the same route. Clinical outcomes reflected these data. Resistant birds infected by the intra-tracheal route had an increased prevalence of tumours and shorter survival times compared with those infected by the intra-abdominal route. Susceptible birds infected by the intra-tracheal route became paralysed 10 days after infection. L7 birds had shorter survival times and increased prevalences of tumours than L6 birds. The pathology and viraemia seen with intra-tracheal infection could not be fully replicated by increasing the dose in intra-abdominal infections. We conclude that instillation of infective dust produces a more aggressive infection that depends on the route of entry and form of virus, and not just on the challenge dose. © 2007 Houghton Trust Ltd

Depletion of neutrophils abrogates MMP9 secretion after influenza virus infection.

<p>Neutrophils were depleted by injecting C57BL/6 mice with 400 µg anti-Ly6G antibody (αLy6G) or isotype control (IgG) one day before infection and every other day thereafter. (A) Depletion of Ly6G+ cells in αLy6G-treated C57BL/6 mice (<i>bottom panel</i>) compared to IgG (<i>top panel</i>) was verified by flow cytometric analysis 6 days after infection. (B) Kinetics of weight loss as a percentage of starting weight in uninfected (control, <i>open symbols</i>) and infected (<i>closed symbols</i>) mice treated with the αLy6G (<i>squares</i>) or IgG isotype (<i>circles</i>). (C) MMP9 secretion by cells from BAL and lung from infected mice that were treated with αLy6G (<i>clear bars</i>) or IgG isotype (<i>grey bars</i>) was measured by ELISPOT. (D) Inflammatory cytokine release in airways after neutrophil depletion. BALs were collected 6 days after infection and supernatants assayed by bead array. (B–D) Mean ± SEM (n = 3, representative of two independent experiments). (B–C) Considered significant at *<i>P</i><0.05, ***<i>P</i><0.001.</p