Faculty Bibliography

A recent workshop discussed the recognition of multiple distinct ligands by individual T cell and B cell receptors and the implications of this discovery for lymphocyte biology. The workshop recommends general use of the term polyspecificity because it emphasizes two fundamental aspects, the inherent specificity of receptor recognition and the ability to recognize multiple ligands. Many different examples of polyspecificity and the structural mechanisms were discussed, and the group concluded that polyspecificity is a general, inherent feature of TCR and antibody recognition. This review summarizes the relevance of polyspecificity for lymphocyte development, activation and disease processes

Why some virus-specific CD8 TCR repertoires are diverse and others restricted or 'oligoclonal' has been unknown. We show here that oligoclonality and extreme clonal dominance can be a consequence of T cell cross-reactivity. Lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) encode NP(205-212) epitopes that induce different but highly cross-reactive diverse TCR repertoires. Homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable TCR motifs. However, heterologous viral challenge resulted in a narrow oligoclonal repertoire with dominant clones with unpredictable TCR sequences. This shift in clonal dominance varied with the private, i.e., unique, specificity of the host's TCR repertoire and was simulated using affinity-based computer models. The skewing differences in TCR repertoire following homologous versus heterologous challenge were observed within the same private immune system in mice adoptively reconstituted with memory CD8 T cell pools from the same donor. Conditions driving oligoclonality resulted in an LCMV epitope escape variant in vivo resembling the natural Lassa virus sequence. Thus, T cell oligoclonality, including extremes in clonal dominance, may be a consequence of heterologous immunity and lead to viral escape. This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes

Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44(high)) and some naive (CD44(low)) CD8 T cells are susceptible to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8(+)CD44(high) T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells

Virus-specific memory T cell populations demonstrate plasticity in antigen recognition and in their ability to accommodate new memory T cell populations. The degeneracy of T cell antigen recognition and the flexibility of diverse antigen-specific repertoires allow the host to respond to a multitude of pathogens while accommodating these numerous large memory pools in a finite immune system. These cross-reactive memory T cells can be employed in immune responses and mediate protective immunity, but they can also induce life-threatening immunopathology or impede transplantation tolerance and graft survival. Here we discuss examples of altered viral pathogenesis occurring as a consequence of heterologous T cell immunity and propose models for the maintenance of a dynamic pool of memory cells

It has long been recognized that educational programs and degrees are not equivalent across Europe. Add to this the fact that Europe consists of many different cultures and languages, then it is not surprising that the free circulation of scientists and their job market in the European Union is severely restricted. This is one of several debated causes for the crisis in European biotechnology, which is in danger of succumbing to the competition of North America, Japan, and some of the developing countries. The Universities (even those tradition-ridden), the European University Association, and the European Commission are aware of the danger and plans are in preparation for sweeping organizational and cultural changes. The problem is how long will it take and how long can we afford to wait? A number of biotechnologists and scientists from several institutions and many countries decided, instead of waiting, to make a preliminary move in the right direction. With the help of the European Commission and using European Molecular Biology Organization, European Federation of Biotechnology, and the European University Rectors as references, the European Association for Higher Education in Biotechnology was founded in 1995 by representatives of universities and research institutes. It awards the additional title of European Doctor to PhD graduates showing excellence in biotechnology and/or related Life Science subjects and who are willing to fulfil a program of studies that is both international and interdisciplinary. The present article reports on the first 9 years of this adventure.

This paper describes the basic structure and the developments of IMMSIM, a modified cellular automaton to simulate chance encounters and discrete effects of cell-cell and cell-molecule interactions in the lymphoid system. Thanks to its flexibility, this model has proven a useful tool in theoretical immunology, experimental research and educational applications. Of the various versions available, we show here the most advanced one (IMMMSIM3), that incorporates both humoral and cellular responses. We describe the results obtained by simulating the responses to viral infection, the impact of viral behavior on the quality of response needed to reach a cure, the cooperation/competition relation between cellular and humoral branches and the effect of vaccination. (C) 2002 Published by Elsevier Science B.V

A modern approach to vaccination faces the compound complexity of microorganism behavior and immune response triggering and regulation. Since computational modeling can yield useful guidelines for biological experimentation, we have used IMMSIM(3), a cellular automaton model for simulating humoral- and cell-mediated responses, to explore a wide range of virus-host relations. Sixty-four virtual viruses were generated by an assortment of speed of growth, infectivity level and lethal load. The outcome of the infections, as influenced by the immune response and the bolstering of cures, obtained by vaccine presensitization are illustrated in this first article. The results of the in machina experiments allow us to relate the success rate of responses to certain combinations of viral parameters and by freezing one or the other branch, and to determine that some viruses are more susceptible to humoral, and others to cellular responses, depending either on single parameters or combinations thereof. This finding allows prediction of which infection may be susceptible to polarized ((Th)(1)>Th(2) and Th(1)

PMID: 11115710

ISSN: 0264-410x

CID: 558742