Michael J. Bevan

Antigen presentation to CD8+ T cells: cross-priming in infectious diseases.

Recent studies indicate that, in most types of infections, antigen presentation by professional bone-marrow-derived cells is essential for priming pathogen-specific CD8+ T cells. This is true even in the absence of direct infection of these cells, which indicates that cross-priming is an essential component of the immune response against pathogens.

Responses of CD8(+) T cells to intracellular bacteria.

Recent studies of CD8(+) T cell responses against intracellular bacteria have provided insights into the relevance of the exogenous and endogenous MHC class I presentation pathways during the priming and effector stages. The capacity of these organisms to deliver vaccine antigens, either as bacterial protein or as plasmid DNA expressed by host antigen-presenting cells, has been investigated. Ongoing studies of CD8(+) T cell effector functions suggest the existence of novel pathways of resistance to bacterial infection. These results, together with advances in our understanding of nonclassical MHC class I presentation, reveal the impact of pathogen biology on host immunity to infection.

Driven to autoimmunity: The nod mouse

In the lymphoid system, T cells respond to space or under-crowding by dividing to maintain their numbers. In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes.

H2-M3 restricted presentation of Listeria monocytogenes antigens

Mice atid hutnans possess three linked, highly polymorphic loci which encode the classical MHC class I molecules. These molecules H-2K, D and L in mice and HLA-A, B and C in humans function to present peptides derived from endogenous proteins to CDS* cytotoxic T lymphocytes (CTL) (Hansen et al. 1993). For the most part the peptides presented by MHC class I are generated by the action of protea.somes in the nucleus and cytosol and are transported into the endoplasmic reticulum (ER) by the specialized transporters associated with antigen presentation (TAP), in the ER the association of nascent class I heavy chain and p-2-microgIobulin is stabilized by a peptide thiit binds well to the class I groove. Only then can the MHC molecule leave the ER and traffic to the cell surface. In this way a cell expressing a mutation in a self protein, or one that is infected by a virus, a bacterium or other parasite that inhabits the cytoplasm may be marked for destruction by CTL (Heemels & Ploegh 1995). One well studied example of a pathogen that induces MHC class I restricted immunity is the common food pathogen, Listeria monocytogenes, a Gram-positive organism which accesses the cytoplasm of host cells. The proteins which it secretes or puts on its surface become class I presented peptides for CTL recognition (Pamer 1993).

The Gads (GrpL) adaptor protein regulates T cell homeostasis

Little is known about the role of the Gads (GrpL) adaptor protein in mature T cell populations. In this study we show that the effects of Gads deficiency on murine CD4+ and CD8+ T cells are markedly different. Gads−/− CD4+ T cells were markedly deficient in the spleen and had an activated phenotype and a rapid turnover rate. When transferred into a wild-type host, Gads−/− CD4+ T cells continued to proliferate at a higher rate than wild-type CD4+ T cells, demonstrating a defect in homeostatic proliferation. Gads−/− CD8+ T cells had a memory-like phenotype, produced IFN-γ in response to ex vivo stimulation, and underwent normal homeostatic proliferation in wild-type hosts. Gads−/− T cells had defective TCR-mediated calcium responses, but had normal activation of ERK. Gads−/− CD4+ T cells, but not CD8+ T cells, had a severe block of TCR-mediated proliferation and a high rate of spontaneous cell death and were highly susceptible to CD95-induced apoptosis. This suggests that the rapid turnover of Gads−/− CD4+ T cells is due to a defect in cell survival. The intracellular signaling pathways that regulate homeostasis in CD4+ and CD8+ T cells are clearly different, and the Gads adaptor protein is critical for homeostasis of CD4+ T cells.

From the Thymus to Longevity in the Periphery

An important attribute of the adaptive immune system is the ability to remember a prior encounter with a pathogen; an ability termed immunological memory. Bigger, better, and stronger responses are mounted upon a secondary encounter with the pathogen potentially resulting in clearance of the infection before the development of disease. We will review recent advances in the field of memory CD8(+) T cell differentiation focusing on both intrinsic and extrinsic factors that govern the development of T cell memory.

Immunology: polarizing a T-cell response.

Signals through Notch receptors regulate many developmental decisions. New evidence suggests that this pathway is also involved in dictating the tone of the immune response to infection.

The Specificity of Positive Selection: MHC and Peptides

Most immature T lymphocytes differentiating in the thymus dont make it. The fact that they might successfully rearrange a T-cell receptor {TCR) /? chain gene and then a TCR a chain gene and that these two variable chains may pair and traffic to the cell surface is not sufficient for these cells to achieve maturity and emigrate from the thymus to the peripheral lymphoid organs. Before this emigration can be allowed, the binding specificity of this new., randomly generated TCR is assessed for its potential usefulness in responding to foreign antigen in the periphery. This test is what we refer to as positive selection. Failure means that the immature thymocyte will die in the thymus. The TCR on CD8^ cytotoxic T lymphocytes (CTL) and CD4-^ helper T lymphocytes recognizes a ligand composed of a complex of a fragment of foreign antigen and a major histocompatibility complex (MHC) class I or class H glycoprotein on the antigen-presenting cell. The discovery of this phetiomenon, now referred to as MHC restriction of T-cell recognition, came in the early 7Os and was made possible because the Class I and Class 11 geties of the MHC are extremely polymorphic. Researchers found that virus-induced CDŜ cells from a C3H mouse, for example, could not kill virus-infected target cells from BALB/c mouse (Zinkernagel & Doherty 1979). In a similar way, it was discovered that T helper function was Class II MHC-restricted. Twenty years of research into this phenomenon of MHC restriction have culminated in the realization that peptide fragments of foreign antigens are bound by MHC molecules Tbe crystal