Chemical Features of Peptide Selection by the Class II Histocompatibility Molecules

I summarize here some of our studies on antigen processing and presentation that have taken place in the last several years. Our recent efforts attempt to explain the cellular and chemical basis for T cell recognition of peptide epitopes from protein antigens. I start with a brief introduction to the main features of antigen presentation and proceed to examine our experiments using the model protein hen egg-white lysozyme (HEL). In these experiments we have focused our attention on the class II major histocompatibility (MHC) molecules and their role in the selection and presentation of peptide epitopes to CD4 T cells. I will also include our recent studies on antigen presentation involving the diabetogenic histocompatibility molecules. My purpose in this paper is to review our own studies. Key literature citations are included but they are in no way comprehensive. Protein antigens must be handled by antigen-presenting cells (APC) to be recognized by the T cell system. This interdependency between the T cell and the APC system of cells is the basis of what we have termed the symbiosis between the innate and adaptive immune systems: both cells depend on each other for full activation of the immune response. 1 In general terms, the first encounter with a foreign element is usually made by the cells of the innate system (ie, the macrophages, the dendritic cell system, and the granulocytes). This is best noted in the response to microbial infections. From this first encounter three positive results can emerge. The first result is the release of cytokines from APC. This release affects the biology of the surrounding cells and tissues. This early response immediately poises the cellular adaptive system. Prominent are the vascular changes characteristic of inflammation as the endothelium becomes activated and receptive to the interaction with circulating leukocytes. Also prominent is the cellular migration that occurs, in part modulated by chemokines. Important among the cytokines released by APC are interleukin-12 (IL-12), the family of tumor necrosis factor (TNF) molecules, and IL-1 molecules. In some of our own studies, we described an interaction that took place rapidly after infection with the intracellular pathogen Listeria monocytogenes. 2 This interaction involved IL-12 and TNF and resulted in the stimulation of natural killer (NK) cells to release interferon-γ (IFN-γ). Once IFN-γ was released various cells become activated, in particular the macrophage system. 3 NK cells form part of the very early system of defense and participate in part through their properties of recognizing and lysing infected cells. In the Listeria infection, the prominent role of macrophage → NK interaction was noted best in mice with severe combined immunodeficiency. These mice do not have lymphocytes. They partially resist and control the infection through this interaction, described above, between macrophages and NK cells. 2 The second result is that the APC are involved in antigen presentation and activation of the T cell system. T cells will not recognize protein antigens unless the antigens are taken by APC. This is done by the processing of protein antigens and the generation of peptides that become bound to MHC molecules, as will be described below. A final result is the modulation of the lymphocyte once its receptor for antigen (the T cell antigen receptor, or TCR) has been engaged by the peptide MHC complex of the APC. The APC does this modulation by expressing molecules that promote cell-to-cell contact and the activation of the T cell (ie, costimulatory molecules) 4 and by releasing cytokines that influence the differentiation of T cells to express different cytokine genes. As recorded by the work of Murphy and O’Garra, the release of IL-12 by the APC is a major reason for the differentiation of T cells to a Th1 pattern of differentiation. 5 The reciprocal component of the symbiosis is activation of the innate cellular system by the products of the activated lymphocytes. Prominent among these cytokines is the role of IFN-γ molecules. 3,6,7 Once IFN-γ is released, the macrophage system, for one, becomes activated. The activated macrophage is a highly cytocidal cell that will restrict the growth of intracellular pathogens. 8