Which signal to respond to?

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According to a new model of T cell receptor signaling, generation of alternative polarization axes by a competing signal might determine responsiveness of the cell to a subsequent distal signal.

Lymphocytes can receive multiple external signals at distinct sites on the cell surface during an immune response. But what determines which of the signals the lymphocyte responds to? Russell and colleagues propose a model by which the generation of alternative axes of polarization by a competing signal might determine the responsiveness of the cell to a subsequent distal signal.

Activation of T cells through the T-cell receptor (TCR) involves several dynamic processes, including formation of the immunological synapse and recruitment of the microtubule organizing centre (MTOC). T cells can also be activated through CD46, which is a receptor for complement component 3b but which also directly recognizes several pathogens including measles viruses. Under some conditions, stimulation of T cells through CD46 can limit the response induced through the TCR, and activation through CD46 has been shown to directly promote the development of regulatory T cells. So, the authors examined the effect of the contrasting signals through the TCR and CD46 on cell polarity, immunological synapse formation and T-cell function.

First, the authors showed that stimulation of cytotoxic T cells (CTLs) with beads coated with CD46-specific antibody induced cell polarization and recruitment of the MTOC, CD3 and perforin to the site of ligation. When T cells were pre-incubated with soluble CD46-specific antibody followed by stimulation with dendritic cells (DCs; which activate T cells through the TCR), the interaction between the DC and T cell was not affected. However, recruitment of the MTOC and CD3 molecules to the interface was reduced, indicating that the immunological synapse was not formed. In fact, the MTOC and CD3 molecules were located with CD46, at the distal pole of the T cells. In addition, production of interferon- gamma (IFN gamma ) induced by allogeneic DCs was greatly reduced compared with cells that were not pre-incubated with the soluble CD46-specific antibody. These effects of CD46 ligation on polarization were also induced by the natural ligand measles haemagglutinin. So, ligation of CD46 at a distal site alters normal DC-induced T-cell polarization and function.

These effects of CD46 ligation on polarization are not specific to T cells as they were also observed in natural killer (NK) cells. Ligation of CD46 prevented recruitment of the MTOC and perforin to the interface between the NK cell and its target cell and significantly reduced NK-cell cytotoxicity.

So, the data indicate that a competing external signal through CD46 can alter T-cell or NK-cell polarization towards DCs or target cells, which can inhibit lymphocyte function. An important question for further study is how many other signals can trigger competing axes of polarity. The authors suggest that this model might be a general mechanism by which lymphocytes determine which extracellular signals to respond to.

Olive Leavy

References

Oliaro, J. et al. Ligation of the cell surface receptor, CD46, alters T cell polarity and response to antigen presentation. Proc. Natl Acad. Sci. USA 103, 18685–18690 (2006) | Article | PubMed |