Failure to find holes in the T-cell repertoire

The ability of an animal to respond to a given antigenic peptide depends on its major histocompatibility complex (MHC) type. Some peptides are not immunogenic when combined with a particular form of the MHC-encoded molecule. This non-responsiveness is regulated by immune response (Ir) genes and is thought to arise by one of two distinct mechanisms. Either the MHC-encoded molecules physically fail to interact with the antigen, preventing the activation of T cells with appropriate receptors, or they limit the expressed repertoire of T cell clones so that no T cells are available to be activated by existing complexes of MHC-encoded molecules and antigen. Experimental evidence has been generated to support both mechanisms. However, the relative importance of each has not been clearly established. In this study we started with a peptide that was immunogenic in B10 mice; it was thus known to be able to interact with the MHC molecule, and T cells existed which could recognise the peptide-MHC complex. Based on previous experiments, we then changed only those parts of the peptide that we thought interacted with the T-cell receptor. All the new analogues created were still immunogenic, confirming that the amino-acid substitutions that we had made did not prevent productive interactions with the MHC-encoded molecule. No limitations ('holes') in the T-cell repertoire were found. The experiments demonstrate the vast potential of the T-cell population to recognize many different analogues, each in a unique way, and suggest that constraints on the diversity of the T-cell repertoire may not be a major explanation for Ir gene defects.     

Differential expression of two distinct T-cell receptors during thymocyte development

The product of the T-cell receptor (TCR) gamma-gene has recently been found to be expressed on a subset of both peripheral cells and thymocytes. As an initial approach to understanding the role of this gamma-chain of TCR (TCR gamma) in T-cell development, we have studied the ontogeny of TCR expression at the protein level in the developing murine thymus. We show here that the first T3-associated TCR to be expressed in the developing thymus is a disulphide-linked heterodimer composed of a gamma-chain of relative molecular mass 35,000 (Mr 35K) and a 45K partner (termed TCR delta). This TCR gamma delta is first detected approximately two days before the appearance of cell-surface TCR alpha beta heterodimers. We report that N-glycosidase digestions reveal that all of the gamma-protein expressed on fetal thymocytes, as in adult CD4-8-(L3T4-, Lyt2-) thymocytes, bear N-linked carbohydrate side chains. The major gamma-gene transcribed in mature, alpha beta-bearing T cells (V gamma 1.2C gamma 2)encodes no N-linked glycosylation site so these results suggest that the fetal gamma delta receptor defines a distinct T-cell lineage whose development in the thymus precedes classical alpha beta-bearing cells.     

Intestinal homeostasis and its breakdown in inflammatory bowel disease

Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease.     

Cytotoxic T cells specific for the circumsporozoite protein of Plasmodium falciparum

Malaria is initiated by the inoculation of a susceptible host with sporozoites from an infected mosquito. The sporozoites enter hepatocytes and develop for a period as exoerythrocyte or hepatic stage parasites. Vaccination with irradiated sporozoites can provide protective immunity and a recent study shows that this can also be conferred by immunization with a recombinant salmonella expressing only the circumsporozoite protein that normally covers the sporozoites. Protection against infection is likely to be mediated by cytotoxic CD8+ cells, as depletion of CD8+ T cells in a sporozoite-immunized animal can completely abrogate immunity. Here we demonstrate directly the existence of CD8+ cytotoxic T lymphocytes (CTL) that recognize the circumsporozoite protein. B10.BR mice immunized with sporozoites or with recombinant vaccinia virus expressing the CS protein of Plasmodium falciparum contain CTL that specifically kill L cell fibroblasts transfected with the gene encoding the same CS protein. The peptide epitope from the CS protein that is recognized by CTL from this strain of mice is from a variant region of the protein.     

A T3-like protein complex associated with the antigen receptor on murine T cells

Antigen recognition by human T lymphocytes and initiation of T-cell activation are mediated by a group of integral membrane proteins, the T-cell antigen receptor (TCR) and the T3 complex. The polypeptides which comprise T3 (a gamma-chain of relative molecular mass (Mr) 25,000 (25K), and delta and epsilon chains of 20K each) are physically associated with the TCR chains. Surface expression of the complex requires the presence of all the component T3 and TCR proteins. In contrast to the human system, murine T3 has not been identified using antibodies. Here we describe a murine T3-like protein complex. It appears to be more complicated than human T3, containing three monomeric glycoproteins (21-28K), two of which have N-linked carbohydrate side chains and a novel family of TCR-associated homo- and heterodimers. The 28K protein is identified as the murine T3 delta-chain. The 21K protein is phosphorylated on cell activation with concanavalin A (Con A).