Helper T cells hunt in the lymph nodes for just the right combination of antigen and its presenting MHC class II molecule (MHCII). But most of the time, they instead find self antigen-MHCII pairs that do not elicit T cell activation.
Fischer et al. investigated the role of these persistent self-interactions by studying mice that lack MHCII. They injected these mice with T cells carrying a receptor specific for an ovalbumin peptide. When the mice were then given normal dendritic cells presenting the ovalbumin antigen, the T cells were apathetic–they did not mount their normal immune responses. And the longer the T cells spent in the MCHII-free mice before seeing the antigen, the more apathetic they became.
The authors traced this growing indifference to a failure of the T cells to meet up with cells carrying their antigen. Normally, these two cell populations quickly overlap in the lymph nodes. But in the MHCII-lacking mice, they were more often found apart. And the T cells were unusually lethargic compared with those in normal lymph nodes.
“If the T cells can't move, they can't actively seek out and find their given antigen,” says Ingulli. “Crawling across all these self signals, it's what makes the T cells move through the lymph nodes. Then they can peruse the dendritic cells, asking ‘who’s got my antigen?'”
The slow T cells were lacking in activated Rap1 and Rac–small GTPases that are known for stimulating motility. Ingulli assumes that the GTPases are turned on by interactions between self-ligands/MHCII and the T cell receptors. “It's a little tickling through the T cell receptor,” she says. “It creates a baseline signaling, but not enough to get the T cell fully activated.” Now she wants to better dissect this signaling pathway.