Immunotherapy

Optimization of a self antigen for presentation of multiple epitopes in cancer immunity. Guevara-Patiño, J. A. et al. J. Clin. Invest. 116, 1382–1390 (2006)

Activation of T cells that recognize self-antigens that are expressed by cancer cells is limited by T-cell tolerance to self-antigens. The authors examined the possibility that enhanced antigen presentation of multiple epitopes could generate multivalent CD8+ T-cell responses. To do this, rationally selected point mutations that create altered peptide ligands were introduced into the gene that encodes tyrosinase-related protein 1 (TYRP1), which is a non-immunogenic self-antigen that is highly expressed by melanoma cells. These mutations caused enhanced protein trafficking, and processing and presentation of various epitopes. Immunization of mice with mutant Tyrp1 DNA after tumour challenge elicited a multi-epitope, CD8+ T-cell response that led to rejection of a melanoma that was only weakly immunogenic and to prolonged survival. Therefore, rationally designed DNA vaccines can elicit T-cell responses against multiple non-mutated epitopes of the self-antigen.

Phagocytosis

Apoptotic cells promote macrophage survival by releasing the anti-apoptotic mediator sphingosine-1-phosphate. Weigert, A. et al. Blood 11 May 2006 (doi:10.1182/blood-2006-04-014852)

Phagocytosis of apoptotic cells by macrophages is an integral part of maintaining cellular homeostasis. Once they have engulfed apoptotic cells, macrophages are protected from apoptosis. Weigert et al. have attributed this protection to the release of sphingosine-1-phosphate (S1P) by the apoptotic cell. This protection of macrophages by S1P involves the activation of survival signals that depend on phosphatidylinositol 3-kinase (PI3K), extracellular-signal-regulated kinase (ERK) and calcium. Upregulation of the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and BCL-XL, as well as inactivation of the pro-apoptotic protein BCL-2-agonistic of cell death (BAD), are also involved in this protective process. Therefore, apoptotic cells have an active role, through the secretion of S1P, in preventing apoptosis of phagocytes, such as macrophages.

Mucosal immunology

Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. Lotz, M. et al. J. Exp. Med. 203, 973–984 (2006)

The functional relevance of Toll-like receptor (TLR) expression by intestinal epithelial cells (IECs) remains unresolved. Lotz et al. showed that fetal, neonatal and adult IECs all expressed the TLR4–MD2 receptor complex. However, only fetal IECs responded to lipopolysaccharide (LPS) stimulation. Postnatal acquisition of LPS tolerance was preceded by a rapid, strong but transient activation of IECs by endogenous endotoxin. Importantly, this spontaneous activation was only observed in vaginally born mice and not in mice delivered by Caesarean section. The postnatal loss of LPS responsiveness was associated with a downregulation of the TLR-signalling molecule interleukin-1-receptor-associated kinase 1 (IRAK1). This phenomenon of acquired unresponsiveness is unique to postnatal IECs, as intestinal macrophages show a constitutive, age-independent, unresponsive phenotype.