Christine Pasero

LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell‐dependent B cell terminal differentiation

The T cell‐dependent differentiation and function of B lymphocytes are tightly regulated by TNF ligands (L) and receptors interactions, such as CD40/CD40L, CD27/CD70 and CD134/CD314L. The LIGHT/HVEM system [homologous to lymphotoxin, inducible expression, competing for GpD of herpes virus, that binds to the herpes virus entry mediator (HVEM), and is expressed on activated T lymphocytes) focused our attention since HVEM has a large distribution that, in addition to T cells, DC or NK, includes tumor and normal B lymphocytes. HVEM was expressed on memory and naive B cells from peripheral blood or tonsils, but not on germinal center (GC) B cells. Costimulation by CD40L+LIGHT induced LIGHT expression at the B lymphocyte surface by a transcriptional mechanism since we detected de novo expression of LIGHT‐specific mRNA. LIGHT expression was further enhanced by triggering of surface IgM, a stimulus that mimics a normal step of B cell physiology, i.e. specific antigen encounter. Stimulation by LIGHT increased the B cell proliferation induced by CD40L, and induced IgG and IgM (but not IgA) secretion. We conclude that LIGHT costimulation, that mimics the B cell encounter with activated LIGHT‐expressing T lymphocytes, enhances both B cell proliferation and Ig production, and thus has a central importance for humoral immunity development.

Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity

Despite the powerful aspects of immune reactions, most often tumor cells are able to evade immune recognition and destruction. Cosignaling molecules from the B7/CD28 and TNF/TNFR superfamilies emerge as novel targets in immunotherapy. Upregulation of coinhibitory molecules by the tumor cells or tumor-infiltrating lymphocytes clearly attenuates T-cell responses against cancer and appears to be a mechanism exerted by the tumor to escape immune response. Today, a variety of coinhibitory molecules, including CTLA-4 and PD1 have been implicated in immune escape of cancer cells. Antagonist antibodies are developed to overcome immune evasion and until now anti-CTLA-4 and anti-PD1 antibodies have been tested in clinical trials with encouraging results. Here we summarize the recent advances made on PD1/PD1 ligands expression in cancer and we discuss about another couple of inhibitory molecules, BTLA and its ligand HVEM and their potential role in immune escape. Such information may provide novel therapeutic targets to reverse tumor-induced T-cell dysfunction in patients with advanced cancers.

CD45 Isoform Profile Identifies Natural Killer (NK) Subsets with Differential Activity.

The leucocyte-specific phosphatase CD45 is present in two main isoforms: the large CD45RA and the short CD45RO. We have recently shown that distinctive expression of these isoforms distinguishes natural killer (NK) populations. For example, co-expression of both isoforms identifies in vivo the anti tumor NK cells in hematological cancer patients. Here we show that low CD45 expression associates with less mature, CD56bright, NK cells. Most NK cells in healthy human donors are CD45RA+CD45RO-. The CD45RA-RO+ phenotype, CD45RO cells, is extremely uncommon in B or NK cells, in contrast to T cells. However, healthy donors possess CD45RAdimRO- (CD45RAdim cells), which show immature markers and are largely expanded in hematopoietic stem cell transplant patients. Blood borne cancer patients also have more CD45RAdim cells that carry several features of immature NK cells. However, and in opposition to their association to NK cell progenitors, they do not proliferate and show low expression of the transferrin receptor protein 1/CD71, suggesting low metabolic activity. Moreover, CD45RAdim cells properly respond to in vitro encounter with target cells by degranulating or gaining CD69 expression. In summary, they are quiescent NK cells, with low metabolic status that can, however, respond after encounter with target cells.

New insights into the regulation of γδ T cells by BTN3A and other BTN/BTNL in tumor immunity

Recent findings in the immunology field have pointed out the emergent role of butyrophilins/butyrophilin-like molecules (BTN/BTNL in human, Btn/Btnl in mouse) in the modulation of γδ T cells. As long as the field develops exponentially, new relationships between certain γδ T cell subsets, on one hand, and their BTN/BTNL counterparts mainly present on epithelial and tumor cells, on the other, are described in the scientific literature. Btnl1/Btnl6 in mice and BTNL3/BTNL8 in humans regulate the homing and maturation of Vγ7+ and Vγ4+ T cells to the gut epithelium. Similarly, Skint-1 has shown to shape the dendritic epidermal T cells repertoire and their activation levels in mice. We and others have identified BTN3A proteins are the key mediators of phosphoantigen sensing by human Vγ9Vδ2 T cells. Here, we first synthesize the modulation of specific γδ T cell subsets by related BTN/BTNL molecules, in human and mice. Then, we focus on the role of BTN3A in the activation of Vγ9Vδ2 T cells, and we highlight the recent advances in the understanding of the expression, regulation, and function of BTN3A in tumor immunity. Hence, recent studies demonstrated that several signals induced by cancer cells or their microenvironment can regulate the expression of BTN3A. Moreover, antibodies targeting BTN3A have shown in vitro and in vivo efficacy in human tumors such as acute myeloid leukemia or pancreatic cancer. We thus finally discuss how these findings could help develop novel γδ T cell-based immunotherapeutical approaches.