Nature Immunology pp 27 - 32

Like any competitive sport, your immune system needs to field its best players in order to win the match against pathogens. Investigators report in the January issue of Nature Immunology that T cells aggressively compete with one another for access to the bits of antigen sitting on "antigen-presenting cells". This struggle ultimately benefits the host, as only the most effective T cells survive, honing the immune response to a fine point in the hopes of "tipping the scales" against the foreign invaders.

Ross Kedl, working with Pippa Marrack and colleagues at the National Jewish Medical Research Center in Denver, shows that when T cells with a range of abilities to bind antigens are vying for access to antigen-presenting cells, only the T cells with the best binding get much "face time". These "high-affinity" T cells dominate the antigen-presenting cells, virtually excluding the lower-affinity T cells. And part of the strategic plan entails the stripping of antigen from the surface of the presenting cell, thus making interactions with lower affinity T cells almost impossible. It's this type of competition that leads to consistently better immune responses � and good immunization.

Nature Immunology pp 42 - 47

T cells don't fight infections from particular viruses or bacteria until they somehow perceive that they are needed. Special cells, called antigen-presenting cells (APCs), get the T cell's attention with very specific, tiny, bits of pathogen. In the January issue of Nature Immunology, scientists from Stanford University show that, paradoxically, to achieve the strongest response, completely unrelated bits of protein, normally from the host itself, must also be carried into the zone of contact between the two cells, called the "immunological synapse".

This surprising result was found during a study of the discrete geometrical patterns of key receptor-ligand molecules that accumulate at the immunological synapse. Mark Davis and colleagues tracked the nonspecific bits (peptides), by fluorescently tagging the molecule that offers the bits to the T cell, the major histocompatibility complex (MHC) proteins. They then used video microscopy to directly watch the peptide-MHC complexes flow along the surface and form the synapse. Even though the "nonspecific bits" of peptides in their test system could not contact the T cell recognition unit itself (they are considered nonspecific because they don't have the right shape to make the contacts), they accumulated in the synapse anyway and enhanced the activation of the T cell. Illuminating this intricate dance at the interface has revealed, therefore, that although specificity is the bedrock upon which all of T cell biology is understood, the system cannot function optimally without contributions from the nonspecific, as well.

Nature Immunology pp 83 - 90

Long-term immunity from tumors requires the generation of memory T cells, but it's not clear how this happens or why it often does not. A report in the January issue of Nature Immunology shows that if tumors are initially marked by a particular protein (CD70) that is recognized by "natural killer" (NK) cells, immune memory responses are elicited and killer T cells can be generated that protect against future exposure of the host to the tumor. Thus, anti-tumor approaches may be made more effective by including activation of NK cells via CD70 recognition.

NK cells (named as such because they are present "naturally", i.e. they are a wandering early-warning system) form part of the innate immune system and have an innate ability to recognize cells that have been damaged through oncogenic transformation. Naturally arising tumors often lose expression of major histocompatibility complex (MHC) proteins, which are surface molecules recognized by cytolytic (killer) T cells. Without these proteins as tags, tumor cells often evade surveillance by the professional immune system. Smyth and colleagues at the Peter MacCallum Cancer Institute in East Melbourne, Australia looked at anti-tumor responses to tumors bearing the CD70 protein. This protein was originally identified in the tumor cells of Hodgkin's lymphoma; it binds the NK cell protein called CD27. The authors found that NK cell recognition of the initial tumor challenge was essential to the development of immunity against tumors that lost their MHC antigens and for memory responses by killer T cells to related tumors. This potent anti-tumor activity depended on NK production of interferon-gamma. Thus, NK cells provide potent signals that link innate tumor responses to long-term tumor immunity.

Nature Immunology pp 61 - 68

Antigen-presenting cells (APCs) offer up peptides to T cells; if the T cell can bind to the peptide, a specific immune response is initiated. A report in the January issue of Nature Immunology identifies preformed microdomains in the plasma membrane of the APCs that are filled with tetraspan proteins (peculiar proteins that weave in-and-out of the membrane four times) and are enriched in specific peptide-MHC complexes. T cell activation requires this focused organization of peptides within the tetraspan domain, thus challenging the idea that antigen clustering occurs only after the APC encounters the T cell.

How do APCs sort the necessary proteins into an organized structure that then elicits appropriate immune responses in a rapid time frame? Harald Kropshofer and colleagues at the Roche Center for Medical Genomics (formerly the Basel Institute for Immunology, Basel, Switzerland) demonstrate that on APC surfaces, specific peptides are enriched in clusters of MHC class II molecules and B cell activation marker CDw78. They found that these microdomains also contain the tetraspan proteins CD9, CD81 and CD82 and the MHC-peptide editor HLA-DM. HLA-DM may be responsible for the limited repertoire of peptides found in these surface microdomains. Tetraspan domains are distinct from lipid rafts (another type of specialized membrane domain), and without them APCs elicit poor T cell responses. Thus tetraspan domains are important in initiating immune responses and immune activation models that only focus on lipid rafts need modification.