Steven Kozlowski

Minimal requirements for peptide mediated activation of CD8+ CTL.

A physical chemical model of T cell stimulation by class I-peptide complexes was developed and used to analyse in vitro studies of gamma-interferon release as a function of the number of peptide and MHC molecules. The analysis provided reasonable estimates of well identified parameters, including equilibrium constants and the minimum number of T cell receptor-class I-peptide ternary complexes on a presenting cell required to activate T cells. The latter number was estimated as 3-5 per T cell. This is in distinct contrast to estimates in the literature of the number of peptide-MHC complexes required for activity, which is necessarily larger. The analysis also predicted that activity is potentiated by interaction between class I molecules, even if one member of the pair is not bound by antigen. The analytical approach used in this paper may be applicable to other activation systems.

Multivalent Requirement for the Stimulation of Alloreactive T Cells: Studies with Engineered Soluble MHC Class I Proteins In Vitro and In Vivo

The murine class I major histocompatibility antigens play critical roles in the interaction of class I-restricted T cell receptors with their stimulatory or target antigen presenting cells. One approach taken by our laboratories has been to investigate the biological activity of genetically engineered, soluble, homogenous, purified class I molecules in the stimulation and inhibition of allospecific T cell hybridomas (Margulies et al, 1986; McCluskey et al, 1988; Schneck et al, 1989a). More recently we have established a system for comparing the role of the cell surface multivalent display of the MHC molecule with these monovalent soluble analogues expressed in vivo in transgenic mice. In this brief review, we hope to recount the logic by which the initial soluble class I MHC molecules were generated, summarize previously published as well as unpublished data on their expression and function, and present some preliminary evidence suggesting that transgenic mice expressing soluble analogues of the H-2Dd protein in a C57B1/6 background will be useful for studies of the molecular and biochemical basis of the generation of immunological tolerance to class I molecules.

Class I MHC/Peptide/ β 2-Microglobulin Interactions:The Basis of Cytotoxic T-Cell Recognition

The past decade has witnessed a major revolution in our thinking and understanding of the molecular basis of T-cell recognition. In this brief review we outline the historical development of this knowledge and how it has drawn upon advances in cellular immunology, virology, genetics, molecular biology, and structural biology. The current status of our view of the molecular details is summarized, and an outline of critical molecular and cellular questions for the future is presented.