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Several groups are currently studying the TNF super-family (IL-1, etc.), which includes several members that can send both positive and negative signals to cells. IL-1 was the first costimulatory molecule to be defined, and there is good evidence that it participates in initiating events in the immune response. The best-characterized of the family is the CD40-ligand interaction—antibodies that block this interaction will also impair immune responses, and researchers are now waiting for the combination studies and knockout studies that will demonstrate whether this is the “missing component.” IL-12 helps initiate Th-1 responses, and GM-CSF helps initiate macrophages. Even chemokines have been reported to give costimulation. In short, there are entire families of molecules that could potentially be manipulated in a vaccine strategy.

Cytokine-Induced Apoptosis and Anergy. TNF and fas can also induce apoptosis. But activation in the absence of costimulation sends a negative signal to the T-cell, driving it into a nonresponsive state. The T-cell does not die, although it does function less well than it did before it was given signal 1 alone, and the term “anergy” was borrowed from B-cell research to describe this state. If the anergic T-cell is restimulated by a normal APC with full costimulation, it generally fails to divide and proliferate, primarily because it fails to produce IL-2, the T-cell growth factor. Production of some additional cytokines such as IL-3 and GM-CSF are down by intermediate amounts, but others such as IFN-gamma don’t seem to be affected.

Only when researchers developed a mouse that produced Th-0 cells, which produce both IL-4 and IFN-gamma, were they able to investigate these effects. They found that anergy didn’t significantly decrease the production of either IL-4 or IFN-gamma, but at the same time the cell was blocked from proliferating in response to IL-4. IL-4 can be a growth factor in the same way as IL-2, but in this case the lack of response wasn’t related to shutting off production.

Researchers concluded from this that the cell has a special kind of regulation that stops proliferation—in short, T-cell anergy (at least in vitro) is really a state of growth arrest, possibly involved through a differentiation process. If it occurs very early, however—i.e., after the cell down-regulates IL-2, but before, has had a chance to turn on its IFN-gamma and IL-4 genes—it can also be a mechanism of tolerance, because it prevents cells from expanding and differentiating.

Molecular Basis for Cytokine-Induced Anergy. Researchers are gaining a clearer understanding of the mechanisms that block signal transduction and prevent IL-2 production (for example) in anergized cells. Early studies demonstrated that the intracellular calcium pathway was completely intact. Other studies showed that transactivation through AP-1 was inhibited, and most recently that the problem is in the activation of ras. In particular, they showed that the She, Grb2, and SOS activations were normal, but that downstream events from ras such as RAF and the ERK kinases can activate the Jun kinases and thereby block AP-1. There are a variety of other ways to regulate ras, including

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