ScienceWeek

IMMUNOLOGY: T CELLS AND MHC PROTEINS

The following points are made by Hidde L. Ploegh (Science 2004 304:1262):

1) T cells recognize antigen with great precision. They use receptors that engage unique combinations of short antigenic fragments held in position by major histocompatibility complex (MHC) proteins. The two classes of MHC proteins are each specialized to serve distinct subsets of T cells. Class I MHC proteins are the target molecules recognized by CD8 killer T cells. They obtain peptide ligands for presentation to T cells through proteolysis of antigen in the cytosol of, for example, virally infected cells or tumor cells. Viral proteins present in virally infected cells are subjected to proteolysis in the cytosol, and the resulting peptides are presented at the cell surface in a complex with class I MHC proteins. This MHC-peptide combination indicates to the CD8 killer T cells that there is a bona fide target that must be eliminated. How such peptides contribute to the priming of naïve CD8 T cells to initiate this immune response is a complicated affair.(1,2)

2) The mere presence of the appropriate MHC-peptide combination is sufficient to engage committed CD8 killer T cells to destroy virally infected cells or tumor cells. However, priming of a T cell response also requires that T cells perceive the correct costimulatory molecules on the surface of professional antigen-presenting cells (APCs), such as dendritic cells. Many viruses, because of their pronounced tropism, do not infect professional APCs, and this raises the question of how a T cell response against such viruses can be initiated at all. Most immunologists now agree that the key is cross-presentation (cross-priming). During cross-presentation, the capture of remnants of virus-infected cells by phagocytosis results in the transfer of viral antigens to professional APCs, which then load the antigen-derived peptides onto their class I MHC proteins (4). The pathways of peptide generation are manifold, as are the proposals for how antigenic proteins or their digestion products leave the phagosomal compartment and arrive in the cytosol. Cross-presentation, in principle, could exploit many different sources of peptide.

3) The peptides produced by cytosolic proteolysis are quite short-lived (seconds rather than minutes) (5) unless they are stabilized by interaction with cytosolic proteins (such as heat shock proteins or chaperones) or by insertion into the peptide-binding groove of class I MHC proteins. The peptides ultimately recognized by T cells in the context of the appropriate MHC proteins are stabilized in two ways: Either they are still embedded in the polypeptides from which they must be liberated by proteolysis, or they are bound as peptides to chaperones or MHC proteins.

References (abridged):

1. M. C. Wolkers, N. Brouwenstijn, A. H. Bakker, M. Toebes, T. N. M. Schumacher, Science 304, 1314 (2004)

2. C. C. Norbury et al., Science 304, 1318 (2004)

3. L. Shen. K. L. Rock, Proc. Natl. Acad. Sci. U.S.A. 101, 3035 (2004)

4. L. J. Sigal et al., Nature 398, 77 (1999)

5. E. Reits et al., Immunity 18, 97 (2003)

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IMMUNOLOGY: ON T CELLS

The following points are made by Jonathan W. Yewdell (Science 2003 301:1334):

1) The adaptive cellular immune system is focused on peptides, which enable it to detect the presence of viruses and other intracellular pathogens. The job of detecting foreign peptides falls to CD8+ T cells. These cells express a clonally restricted receptor that recognizes 8- to 11-residue peptides nestling in the groove of major histocompatibility complex (MHC) class I molecules. Virtually all cell types in humans and other jawed vertebrates continually send class I molecules loaded with cellular peptides to the cell surface. In a process termed "tolerance", T cells directed against class I molecules bearing self peptides are either killed or functionally silenced, preventing autoimmune responses. Following a viral infection, however, newly synthesized class I molecules carry viral peptides to the surface of infected cells. Here they are recognized by nonself-reactive T cells specific for the given peptide-class 1 complex. Activated T cells then deliver a cocktail of immune effector molecules that interfere with viral replication either by brute force (killing the virally infected cell) or by more subtle means (reprogramming the virally infected cell to disfavor viral replication). One of the key features of T cells is their remarkable sensitivity. The most efficient T cells approach the ultimate design limit of recognizing a single peptide-class I complex on the surface of a target cell.

2) Faced with such an adroit opponent, many viruses adopt a hit-and-run strategy, moving from host to host with such rapidity that they don't have to confront T cells, which need time to expand their numbers to cope with the burgeoning infected cell population. Epstein-Barr virus (EBV), however, like other herpesviruses, chooses a different strategy. This virus infects individuals for their entire lives, hiding in certain cell types and only infrequently becoming reactivated to produce new viral progeny that then infect other individuals. EBV evades T cells largely by suppressing the expression of its genes. To maintain latency, however, it must express EBNA1 (Epstein-Barr virus nuclear antigen 1). This protein has an amino-terminal domain composed of a glycine-alanine repeat region (GAr) that prevents its degradation by proteasomes, the macromolecular assemblies that dispose of damaged or unwanted cellular proteins. Most of the peptides presented by class I molecules to T cells are a by-product of this destruction. By blocking proteasome destruction of EBNA1, the GAr region may prevent presentation of EBNA1 peptides to T cells (4).

3) Recent findings, together with earlier clues, have important implications for both cellular immunity and for the general process of decoding genetic information. The "peptidome", that is, the set of all peptides from host and pathogenic genomes presented by class I molecules to the immune system, may be much larger than previously thought. It now seems that peptides can potentially be generated from all DNA sequences in each of the six potential reading frames (three frames on each strand of DNA), and not just from standard genes in standard reading frames. Moreover, because of ribosomal skipping (1), peptides might be derived from noncontiguous sequences in the same or different reading frames. Immunologists, particularly those searching for elusive peptides recognized by tumor-specific T cells, will be disheartened by the new results. Their job of finding a peptide needle in the growing genetic haystack has just become a lot more difficult. Biologists now have to consider the possibility that cells generate polypeptides of potential evolutionary importance from a much larger information store than previously considered.(2,3,5)

References (abridged):

1. R. F. Gesteland, J. F. Atkins, Annu. Rev. Biochem. 65, 741 (1996)

2. S. R. Schwab et al., Science 301, 1367 (2003)

3. Y. Yin et al., Science 301, 1371 (2003)

4. N. P. Dantuma et al., Curr. Top. Microbiol. Immunol. 269, 23 (2002)

5. D. N. Wheatley, M. S. Inglis, Cell Biol. Int. Rep. 9, 463 (1985)

Science http://www.sciencemag.org

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IMMUNOLOGY: T-CELL SYNAPSES

Notes by ScienceWeek:

The so-called "adaptive immune system" of vertebrates, the system that responds in an adaptive manner to specific pathogen-derived or non-pathogenic foreign chemical entities, provides a protective system that distinguishes foreign proteins from the proteins of the organism itself. The foreign material (or part of the foreign material) that is recognized as such by the immune system is denoted by the term "antigen". Usually the antigen is a protein or protein-attached moiety (hapten) that has entered the bloodstream of the animal, e.g., the coat protein of an infecting virus, or the cell-surface protein of a malignant cell. Exposure to an antigen initiates an immune response that specifically recognizes the antigen and destroys it.

Adaptive immune responses are in general the responsibility of white blood cells (leukocytes), particularly the so-called B-and T-lymphocytes (B-cells and T-cells), and in addition large amoeba-like cells called "macrophages". The lymphocytes are named after the tissue that produces them: in mammals, B-cells mature in bone marrow, while T-cells mature in the thymus gland. There are an estimated 10^(12) immune system cells in the human body, enough to constitute a large organ if they were all assembled together. In general, the term "lymphocyte" refers to any cell that circulates in the "lymph", a blood-plasma-like fluid circulating separately but connected to the blood system.

The adaptive immune system has many mechanisms to destroy an antigen invader, with the responses generally categorized into two types, the "humoral response" and the "cell-mediated response".

The humoral response depends primarily on B-cells, aided by certain "helper T-cells" which provoke proliferation of B-cells, and involves the secretion of specific antibodies by B-cells, the antibodies consisting of proteins of the immunoglobulin class that bind to specific antigens.

The cell-mediated immune response is executed by both helper T-cells and a class of T-lymphocytes called cytotoxic T-cells ("killer T-cells"), which attack host cells that have been infected by a pathogen. In the cell-mediated immune response, T-cells may also begin a T-cell proliferation process as a result of contact with an "antigen-presenting cell" (see below), the proliferation involving cellular specialization (differentiation) and the production of a large number of specific-antigen-activated T-cells from a single progenitor cell (clonal expansion).

The basic function of the T-cell in recognizing a target antigen involves the use of T-cell surface receptors to recognize an antigen when it is presented on the surface of another cell, either an infected target cell or an immune system antigen-presenting cell. In the former case, various antigen fragments of the infecting intracellular pathogen are transported to the host-cell surface; in the latter case, immune system cells specialized to present antigens on their surfaces are involved, the antigens derived from engulfment (phagocytosis) and fragmentation of the pathogen. In both cases, the antigen is presented on the cell surface by a special protein called "major histocompatibility complex" (MHC), and in order for the antigen to be recognized by the T-cell, the antigen must be presented by one of the MHC group of proteins. It is apparently the combination of the antigen peptide fragment and MHC protein which is recognized by the T-cell receptor.

In general, then, T-cells have various roles in immune responses: there are types of T-cells involved in the humoral immune response and types of T-cells involved in the cell-mediated immune response. But in both cases, T-cell receptors interact with antigen-MHC complexes presented by an "antigen-presenting cell": in the case of the humoral immune response, the antigen-presenting cell is a host immune system cell which presents to the T-cells an antigen-MHC entity derived from the pathogen, and the T-cells (in this case, helper T-cells) are then involved in antibody production by B-cells; in the case of the cell-mediated immune response, the antigen-MHC-presenting cell is an infected host cell, the responding T-cells are helper T-cells and cytotoxic T-cells, with both helper T-cells and cytotoxic T-cells indirectly and directly involved, respectively, in the destruction of the infected host cell. Another generalization is that the humoral immune response is primarily directed against extracellular pathogens or pathogen derivatives, while the cell-mediated immune response is primarily directed against intracellular pathogens (or, in special cases, malignant host or foreign tissue cells).

There is some evidence that when T-cell proliferation occurs, a sustained engagement of T-cell receptors with antigen-presenting host-cell surface complexes is necessary, with the recognition by the T-cell of an antigen-MHC entity then involving an actual long-term (e.g., minutes or hours) juxtaposition of the T-cell and antigen-presenting cell. This juxtaposition, the details of which are not yet clearly understood, is called the "immunological synapse". The physical juxtaposition of the cells, an actual binding of their two surfaces at one or more points, is apparently mediated by so-called "adhesion molecules", which are active not only in relation to immunological synapses, but also in relation to other processes involving both intercellular adhesion and adhesion of cells to the extracellular macromolecular matrix. Recent evidence indicates the immunological synapse consists of a central cluster of T-cell receptors surrounded by a ring of adhesion molecules.

The following points are made by A. Grakoui et al (Science 1999 285:221):

1) The authors present an experimental study of immunological synapses, the study including real-time imaging and quantitative analysis of a model system consisting of planar lipid bilayers on glass supports mimicking the plasma membranes of antigen-presenting cells. The authors incorporated fluorescent-labelled MHC peptides and relevant adhesion molecules into the bilayers, and then added living T-cells to the system, the T-cells forming points of contact with ligands in the bilayer.

2) The authors report their results indicate that immunological synapse formation involves an active and dynamic mechanism that allows T-cells to distinguish potential antigenic ligands. Initially, T-cell receptor ligands are engaged in an outermost ring of the nascent synapse. Transport of these complexes into the central cluster is dependent on T-cell receptor-ligand interaction kinetics. Finally, formation of a stable central cluster at the heart of the synapse is apparently a determinative event for T-cell proliferation.

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