Stress proteins and the immune response

The heat shock or stress response is one of the most highly conserved adapt ive responses in nature. In single cell organisms, the stress response conf ers tolerance to a variety of stresses including hyperthermia, hyperoxia, h ypoxia, and other perturbations, which alter protein synthesis. This tolera nce phenomenon is also extremely important in the multicellular organism, r esulting in not only thermal tolerance, but also resistance to stresses of the whole organism such as ischemia-reperfusion injury. Moreover, recent da ta indicates that these stress proteins have the ability to modulate the ce llular immune response. Although the terms heat shock proteins (HSPs) and stress proteins are often used interchangeably, the term stress proteins includes the HSPs, the gluc ose-regulated proteins (GRPs) and ubiquitin. The stress proteins may be gro uped by molecular weight ranging from the large 110 kDa HSP110 to ubiquitin at 8 kDa. These proteins serve as cellular chaperones, participating in pr otein synthesis and transport through the various cellular compartments. Be cause these proteins have unique cellular localizations, the chaperone func tion of the stress proteins often involves a transfer of peptides between s tress proteins as the peptide is moved between cellular compartments. For e xample, HSP70 is a cytosolic and nuclear chaperone, which is critical for t he transfer of cellular peptides in the mitochondrion through a hand-off th at involves mitochondrial HSP60 at the inner mitochondrial membrane. Simila rly, cytosolic proteins are transferred from HSP70 to gp96 as they move int o the endoplasmic reticulum. The central role of the stress proteins in the transfer of peptides through the cell may be responsible for the recently recognized importance of the stress proteins in the modulation of the immune system [Feder, M.E., Hofman n, G.E., 1999. Heat-shock proteins, molecular chaperones, and the stress re sponse: evolutionary and ecological physiology. Annu. Rev. Physiol. 61, 243 -282.]. This importance in immune regulation is best addressed using Matzin ger's model of the immune response - The Danger Theory of Immunity [Matzing er, P., Fuchs, E.J., 1996. Beyond self and non-self: immunity is a conversa tion, not a war. J. NIH Res. 8, 35-39.]. Matzinger suggests that an immune system model based on the differentiation between "self and non-self" does not easily account for the changes that occur in the organism with growth a nd development. Why, for example does an organism not self-destruct when th e immune system encounters the myriad of new peptides generated at puberty? Instead, she proposes a model of immune function based on the ability to d etect and address dangers. This model states that the basic function of all cells of the organism is appropriately timed death "from natural causes". This type of cell death, or apoptosis, generates no stress signals. If, on the other hand, a cell is "murdered" by an infectious agent or dies an unti mely death due to necrosis or ischemia, the cell undergoes a stress respons e with the liberation of stress protein-peptide complexes into the extracel lular environment upon cell lysis. Not only do they serve as a "danger sign al" to alert the immune system to the death of a cell under stress, but the ir role as protein carriers allows the immune effector cells to survey the peptides released by this stressed cell and to activate against new or unre cognized peptides carried by the stress protein. Matzinger bases the Danger Theory of Immunity on three "Laws of Lymphotics". These laws state that: ( 1) resting T lymphocytes require both antigen stimulation by an antigen-pre senting cell (APC) and co-stimulation with a danger signal to become activa ted; (2) the co-stimulatory signal must be received through the APC; and (3 ) T cells receiving only antigen stimulation without the co-stimulatory sig nal undergo apoptosis. The Danger Theory gives a simple model for both tole rance and activation. In the previous example of an immune system encounter ing the new peptides of puberty, antigens but not co-stimulatory signals wo uld be presented to T cells. The result would be apoptosis of those T cells recognizing the antigens, and the development of a state of tolerance [Mat zinger, P., 1994. How is self-tolerance induced and maintained. Horror auto toxicus. Annu. Rev. Immunol. 12. 991-1045.]. In the case of infection, a st ressed cell would die and provide the APC danger signals in the form of str ess proteins, and antigens conveniently carried by these same stress protei ns. The APC would then be able to deliver both signals to T cells for activ ation. (C) 2000 Published by Elsevier Science B.V.