Low (gray diamonds) but not high (black square) affinity T cells proliferate in response to MBP presentation.


New results from Antoine Perchellet, Joan Goverman, and colleagues (University of Washington, Seattle, WA) show that T cells that bind self-peptides most avidly can survive and engulf self-peptides without initiating an autoimmune response. Although appearing innocent, these cells might be potential disease instigators.

Most self-recognizing T cells whose receptors interact too strongly with self-peptides are either killed or made unreactive (by receptor rearrangement) in the thymus. If they somehow escape to the bloodstream, they can also be killed or silenced there. To study how these processes eliminate T cell responses to myelin basic protein (MBP), a target of T cells during multiple sclerosis, the authors created two mice lines that express different MBP-specific T cell receptors.

One receptor, which had a lower affinity for MBP, worked as expected—T cells with this receptor were removed from the thymus or later from the periphery. T cells with the higher affinity receptor somehow persisted, however. Yet the mice did not develop autoimmunity, revealing a third route for preventing autoimmune reactions.

The mice remained healthy because the T cells were ineffective even with their high affinity receptor. The T cells did not proliferate in response to MBP presented by dendritic cells because they did not make interleukin-2 (IL-2). The reason for this failure remains unclear, but it seems to lie downstream of MBP recognition. If MBP-presenting dendritic cells were preincubated with high affinity T cells, the dendritic cells could no longer elicit proliferation of low affinity T cells, probably because they had been stripped of MBP.

The mice were problem free, but Goverman says the escaping T cells are still worrisome because they are present in the periphery. “If they get activated by some other mechanism,” she says (by viral infection, for example), “then they'll wake up, see MBP, and attack it. And they see the ligand really well, because they are high affinity.” ▪


Perchellet, A., et al. 2004. Nat. Immunol. 10.1038/ni1073.