Immunology

free up to august

Available evidence indicates that the CD6 lymphocyte surface receptor is involved in T-cell developmental and activation processes, by facilitating cell-to-cell adhesive contacts with antigen presenting cells and likely modulating T-cell receptor (TCR) signaling. Here, we show that in vitro activation of human T-cells under different TCR-ligation conditions leads to surface down-regulation of CD6 expression. This phenomenon was i) concomitant to increased levels of soluble CD6 in culture supernatants, ii) partially reverted by protease inhibitors, iii) no associated down-regulated in CD6 mRNA levels, and iv) reversible by stimulus removal. CD6 down-modulation inversely correlated with up-regulation of CD25 in both FoxP3- (Tact) and FoxP3+ (Treg) cell subsets. Furthermore, ex vivo analysis of peripheral CD4+ and CD8+ T-cells with activated (CD25+) or effector memory (TEM, CD45RA-CCR7-) phenotype present lower CD6 levels than their naïve or central memory (TCM, CD45RA-CCR7+) counterparts. CD6lo/- T-cells resulting from in vitro T-cell activation show higher apoptosis and lower proliferation levels than CD6hi T-cells, supporting the relevance of CD6 in the induction of proper T-cell proliferative responses and resistance to apoptosis. Accordingly, CD6 transfectants also showed higher viability when exposed to TCR-independent apoptosis-inducing conditions in comparison with untransfected cells. Taken together, these results provide insight into the origin of soluble CD6 and the previously reported circulating CD6-negative T-cell subset in humans, as well as into the functional consequences of CD6 down-modulation on ongoing T-cell responses, which includes sensitization to apoptotic events and attenuation of T-cell proliferative responses.

Targeting CD100 by antibody blockade is a potential therapeutic strategy for cancers, but the functional effects on T cells following blockade of this immune activating molecule are rarely considered. Indeed, CD100 is highly expressed in T cells and anti-CD100 antibodies play a role during T cell proliferation, however, the outcome varies from different studies and the underlying mechanism is still unclear. To address this, monoclonal antibody clones directed against CD100 were evaluated. In their soluble form, four of these antibodies significantly reduced the expansion of T cells in the presence of bead-bound anti-CD3/CD28, either in total PBMC or purified T cell culture systems. Similar inhibition was seen when blocking CD100-CD72 interaction by soluble anti-CD72 instead of anti-CD100 antibodies. Conversely, restoring the interaction by CD72-Fc eliminated the soluble anti-CD100 induced inhibitory effect. Taken together, these results reveal that T cell proliferation is regulated by CD100 via interaction with CD72. They further establish an in vitro system to evaluate the inhibitory effect of anti-CD100 antibodies on T cells, to which attention should be paid in clinical trials in order to avoid potential side effects.

Tertiary lymphoid structures (TLSs) have been identified in the parenchyma and/or in the peripheral margins of human solid tumors. Uncovering the functional nature of these structures is the subject of much intensive investigation. Studies have shown a direct correlation of the presence of human tumor-localized TLS and better patient outcome (e.g., increase in overall survival) in certain solid tumor histologies, but not all. We had identified a tumor-derived immune gene expression signature, encoding 12 distinct chemokines, which could reliably identify the presence of TLSs, of different degrees, in a variety of human solid tumors. We are focused on understanding the influence of TLSs on the tumor microenvironment and leveraging this understanding to both manipulate the anti-tumor immune response and potentially enhance immunotherapy applications. Moreover, as not all human solid tumors show the presence of these lymphoid structures, we are embarking on bioengineering approaches to design and build ‘designer’ TLSs to address, and potentially overcome, an unmet medical need in cancer patients whose tumors lack such lymphoid structures.

National Academy of Sciences

Expression of a competent Igh heavy chain initiates a pre-BCR checkpoint during B cell development. Reth and colleagues show that protein arginine methylation by a BTG2-PRMT1 complex is required to inactivate CDK4 and thereby establish pre-B cell arrest.

Background: Defensins are antimicrobial peptides that exert immunomodulatory and chemotactic functions. Based on these properties and their high expression levels in the skin, they are likely to affect skin inflammation, infection, and wound healing. This may lead to therapeutic applications in (burn) wound healing. Objective: We aimed to investigate the effects of human β-defensins (hBDs) on keratinocytes and fibroblasts, 2 major skin cell types involved in skin regeneration. Methods: Monolayer keratinocyte and fibroblast cultures were exposed to recombinant hBDs, and we overexpressed hBD2 and hBD3 in keratinocytes of reconstructed epidermal equivalents by lentiviral transduction. The effects were measured by immunohistochemistry, quantitative real-time PCR, and migration assays. Kinome analyses were performed on cultured keratinocytes to investigate the signal transduction events elicited by hBD stimulation. Results: We found that hBD3 induced the expression of cytokines and chemokines in keratinocytes, which was not observed in fibroblasts. hBD2, however, stimulated cell migration only in fibroblasts, which was not found for hBD3. Both defensins are likely to exert receptor-mediated effects in keratinocytes, as witnessed by changes in protein kinase activation following stimulation by hBD2 and hBD3. Kinome analysis suggested that protein kinase C activation was a common event for both defensins. We observed, however, considerable differences in keratinocyte responses between stimulation by exogenous recombinant defensins and endogenous defensins expressed following lentiviral transduction. Conclusion: Defensins exert modest biological effects on skin cells that are potentially beneficial in wound healing, but many questions regarding the biological mechanisms of action and relevance for the in vivo situation are still remaining.
Dermatology

Platelets participate in many important physiological processes, including hemostasis and immunity. However, despite their broad participation in these evolutionarily critical roles, the anucleate platelet is uniquely mammalian. In contrast with the large nucleated equivalents in lower vertebrates, we find that the design template for the evolutionary specialization of platelets shares remarkable similarities with human-engineered unmanned aerial vehicles in terms of overall autonomy, maneuverability, and expendability. Here, we review evidence illustrating how platelets are uniquely suited for surveillance and the manner in which they consequently provide various types of support to other cell types.

Natural killer cells are important effector lymphocytes of the innate immune system, playing critical roles in anti-tumor and anti-infection host defense. Tumor progression or chronic infections, however, usually leads to exhaustion of NK cells, thus limiting the anti-tumor/infection potential of NK cells. In many tumors or chronic infections, multiple mechanisms might contribute to the exhaustion of NK cells, such as dysregulated NK cell receptors signaling, as well as suppressive effects by regulatory cells or soluble factors within the microenvironment. Better understanding of the characteristics, as well as the underlying mechanisms of NK cell exhaustion, not only should increase our understanding of the basic biology of NK cells, but also could reveal novel NK cell-based anti-tumor/infection targets. Here, we provide an overview of our current knowledge on NK cell exhaustion in tumors, and in chronic infections.

The innate immune response is evolutionary conserved among organisms. The complement system forms an important and efficient immune defense mechanism. It consists of plasma proteins that participate in microbial detection, which ultimately results in the production of various molecules with antimicrobial activity. Thioester-containing proteins (TEPs) are a superfamily of secreted effector proteins. In vertebrates, certain TEPs act in the innate immune response by promoting recruitment of immune cells, phagocytosis, and direct lysis of microbial invaders. Insects are excellent models for dissecting the molecular basis of innate immune recognition and response to a wide range of microbial infections. Impressive progress in recent years has generated crucial information on the role of TEPs in the antibacterial and anti-parasite response of the tractable model insect Drosophila melanogaster and the mosquito malaria vector Anopheles gambiae. This knowledge is critical for better understanding the evolution of TEPs and their involvement in the regulation of the host innate immune system.